923362401@GENIA Treebank@formal@@1@S@In vivo footprinting and mutational analysis of the proximal CD19 promoter reveal important roles for an SP1/Egr-1 binding site and a novel site termed the PyG box.@@@@1@28@@oe@16-12-2010 923362402@GENIA Treebank@formal@@1@S@CD19 expression begins at the pro-B cell stage of B cell development.@@@@1@13@@oe@16-12-2010 923362403@GENIA Treebank@formal@@1@S@As such it serves as a good prototype for B cell-specific genes whose expression begins shortly after lineage commitment.@@@@1@20@@oe@16-12-2010 923362404@GENIA Treebank@formal@@1@S@To understand the molecular mechanisms controlling CD19 gene expression, we isolated and functionally characterized the CD19 promoter using in vivo footprinting, gel shift assays, and transfection studies.@@@@1@31@@oe@16-12-2010 923362405@GENIA Treebank@formal@@1@S@Reporter constructs spanning portions of the promoter identified a region between -85 and -200 that produced high levels of reporter gene activity in lymphoid cells.@@@@1@26@@oe@16-12-2010 923362406@GENIA Treebank@formal@@1@S@In vivo footprinting identified protected regions over the known high affinity B cell lineage-specific activator protein (BSAP) site, the low affinity BSAP site, a SP1/Egr-1 site termed the CD19 GC box, and two novel sites named the AT box and PyG box.@@@@1@48@@oe@16-12-2010 923362407@GENIA Treebank@formal@@1@S@Phorbol ester treatment of a pre-B cell line up-regulated CD19 expression, induced Egr-1, and enhanced the footprint over the GC box.@@@@1@24@@oe@16-12-2010 923362408@GENIA Treebank@formal@@1@S@Gel shift assays demonstrated SP1 and Egr-1 binding to the CD19 GC box, while unknown nuclear proteins bound the PyG and AT boxes.@@@@1@25@@oe@16-12-2010 923362409@GENIA Treebank@formal@@1@S@Mutations in the AT box or in the BSAP sites did not affect CD19 reporter construct activity, while a mutation of the GC box reduced it modestly, and a PyG box mutation reduced it dramatically.@@@@1@38@@oe@16-12-2010 923362410@GENIA Treebank@formal@@1@S@BSAP failed to trans-activate CD19 promoter constructs in B cells or non-B cells, suggesting that cis elements such as the PyG and GC boxes are also necessary for high level CD19 promoter expression.@@@@1@35@@oe@16-12-2010 923362801@GENIA Treebank@formal@@1@S@Involvement of Rel, Fos, and Jun proteins in binding activity to the IL-2 promoter CD28 response element/AP-1 sequence in human T cells.@@@@1@25@@oe@16-12-2010 923362802@GENIA Treebank@formal@@1@S@CD28 is an important costimulatory molecule in the activation of human T cells.@@@@1@14@@oe@16-12-2010 923362803@GENIA Treebank@formal@@1@S@Costimulation of T cells through both the Ag receptor and CD28 leads to high level IL-2 production, which is vital to the development of an immune response in vivo.@@@@1@31@@oe@16-12-2010 923362804@GENIA Treebank@formal@@1@S@Previous reports have suggested the CD28 stimulation contributes to the activation of the IL-2 promoter by up-regulating the activity of several transcription factors, including AP-1 and nuclear factor-kappaB (NF-kappaB)/Rel family members as well as an uncharacterized transcription factor called CD28 response complex.@@@@1@47@@oe@16-12-2010 923362805@GENIA Treebank@formal@@1@S@While several lines of investigation have suggested that NF-kappaB/Rel family members make up the CD28 response complex transcription factor, other work has not supported this conclusion.@@@@1@28@@oe@16-12-2010 923362806@GENIA Treebank@formal@@1@S@Recent studies suggest that the CD28 response element (CD28RE) does not function independently but works instead in conjunction with the adjacent promoter proximal AP-1-binding site and this hypothesis is confirmed here.@@@@1@34@@oe@16-12-2010 923362807@GENIA Treebank@formal@@1@S@Also in the current study, binding activity to the CD28RE/AP-1 sequence of the IL-2 promoter is evaluated.@@@@1@19@@oe@16-12-2010 923362808@GENIA Treebank@formal@@1@S@Although four specific complexes can be detected binding to this sequence, only one of these complexes is specific for both the CD28RE and the adjacent AP-1 site.@@@@1@29@@oe@16-12-2010 923362809@GENIA Treebank@formal@@1@S@Of the NF-kappaB/Rel family members tested, this CD28RE/AP-1-specific complex contains predominantly c-Rel, despite the fact that both p50 and RelA can efficiently bind to the CD28RE.@@@@1@29@@oe@16-12-2010 923362810@GENIA Treebank@formal@@1@S@c-Fos and c-Jun are also found in this CD28RE/AP-1-specific complex.@@@@1@11@@oe@16-12-2010 923362811@GENIA Treebank@formal@@1@S@These data indicate that functional complexes encompassing both the CD28RE and the AP-1-binding sites influence IL-2 promoter activity in CD28-costimulated T cells.@@@@1@23@@oe@16-12-2010 923380201@GENIA Treebank@formal@@1@S@c-Myb and Ets proteins synergize to overcome transcriptional repression by ZEB.@@@@1@12@@oe@16-12-2010 923380202@GENIA Treebank@formal@@1@S@The Zfh family of zinc finger/homeodomain proteins was first identified in Drosophila where it is required for differentiation of tissues such as the central nervous system and muscle.@@@@1@29@@oe@16-12-2010 923380203@GENIA Treebank@formal@@1@S@ZEB, a vertebrate homolog of Zfh-1, binds a subset of E boxes and blocks myogenesis through transcriptional repression of muscle genes.@@@@1@24@@oe@16-12-2010 923380204@GENIA Treebank@formal@@1@S@We present evidence here that ZEB also has an important role in controlling hematopoietic gene transcription.@@@@1@17@@oe@16-12-2010 923380205@GENIA Treebank@formal@@1@S@Two families of transcription factors that are required for normal hematopoiesis are c-Myb and Ets.@@@@1@16@@oe@16-12-2010 923380206@GENIA Treebank@formal@@1@S@These factors act synergistically to activate transcription, and this synergy is required for transcription of at least several important hematopoietic genes.@@@@1@23@@oe@16-12-2010 923380207@GENIA Treebank@formal@@1@S@ZEB blocks the activity of c-Myb and Ets individually, but together the factors synergize to resist this repression.@@@@1@20@@oe@16-12-2010 923380208@GENIA Treebank@formal@@1@S@Such repression imposes a requirement for both c-Myb and Ets for transcriptional activity, providing one explanation for why synergy between these factors is important.@@@@1@26@@oe@16-12-2010 923380209@GENIA Treebank@formal@@1@S@The balance between repression by ZEB and transcriptional activation by c-Myb/Ets provides a flexible regulatory mechanism for controlling gene expression in hematopoietic cells.@@@@1@24@@oe@16-12-2010 923380210@GENIA Treebank@formal@@1@S@We demonstrate that one target of this positive/negative regulation in vivo is the alpha4 integrin, which play a key role in normal hematopoiesis and function of mature leukocytes.@@@@1@30@@oe@16-12-2010 923467901@GENIA Treebank@formal@@1@S@A conserved tissue-specific structure at a human T-cell receptor beta-chain core promoter.@@@@1@13@@oe@16-12-2010 923467902@GENIA Treebank@formal@@1@S@The T-cell receptor (TCR) beta-chain promoters have been characterized as nonstructured basal promoters that carry a single conserved ubiquitous cyclic AMP-responsive element.@@@@1@25@@oe@16-12-2010 923467903@GENIA Treebank@formal@@1@S@Our investigation of the human TCR beta gene uncovers a surprisingly complex and tissue-specific structure at the TCR Vbeta 8.1 promoter.@@@@1@22@@oe@16-12-2010 923467904@GENIA Treebank@formal@@1@S@The core of the promoter (positions -42 to +11) is recognized by the lymphoid cell-specific transcription factors Ets-1, LEF1, and AML1 as well as by CREB/ATF-1, as is demonstrated in gel shift and footprinting experiments.@@@@1@41@@oe@16-12-2010 923467905@GENIA Treebank@formal@@1@S@With the exception of LEF1, these factors activate transcription in T cells.@@@@1@14@@oe@16-12-2010 923467906@GENIA Treebank@formal@@1@S@Binding sites at the core region show little conservation with consensus sites.@@@@1@13@@oe@16-12-2010 923467907@GENIA Treebank@formal@@1@S@Nonetheless, CREB, Ets-1, and AML1 bind and activate cooperatively and very efficiently through the nonconsensus binding sites at the core promoter region.@@@@1@26@@oe@16-12-2010 923467908@GENIA Treebank@formal@@1@S@Moderate ubiquitous activation is further induced by CREB/ATF and Sp1 factors through proximal upstream elements.@@@@1@16@@oe@16-12-2010 923467909@GENIA Treebank@formal@@1@S@The tissue-specific core promoter structure is apparently conserved in other T-cell-specifically expressed genes such as the CD4 gene.@@@@1@19@@oe@16-12-2010 923467910@GENIA Treebank@formal@@1@S@Our observations suggest that both the enhancer and the promoter have a complex tissue-specific structure whose functional interplay potentiates T-cell-specific transcription.@@@@1@22@@oe@16-12-2010 923469601@GENIA Treebank@formal@@1@S@GABP factors bind to a distal interleukin 2 (IL-2) enhancer and contribute to c-Raf-mediated increase in IL-2 induction.@@@@1@21@@oe@16-12-2010 923469602@GENIA Treebank@formal@@1@S@Triggering of the T-cell receptor-CD3 complex activates two major signal cascades in T lymphocytes, (i) Ca2+-dependent signal cascades and (ii) protein kinase cascades.@@@@1@29@@oe@16-12-2010 923469603@GENIA Treebank@formal@@1@S@Both signal cascades contribute to the induction of the interleukin 2 (IL-2) gene during T-cell activation.@@@@1@19@@oe@16-12-2010 923469604@GENIA Treebank@formal@@1@S@Prominent protein kinase cascades are those that activate mitogen-activated protein (MAP) kinases.@@@@1@15@@oe@16-12-2010 923469605@GENIA Treebank@formal@@1@S@We show here that c-Raf, which is at the helm of the classic MAP-Erk cascade, contributes to IL-2 induction through a distal enhancer element spanning the nucleotides from positions -502 to -413 in front of the transcriptional start site of the IL-2 gene.@@@@1@46@@oe@16-12-2010 923469606@GENIA Treebank@formal@@1@S@Induction of this distal IL-2 enhancer differs from induction of the proximal IL-2 promoter-enhancer, since it is induced by phorbol esters alone and independent from Ca2+ signals.@@@@1@29@@oe@16-12-2010 923469607@GENIA Treebank@formal@@1@S@In DNA-protein binding studies, we detected the binding of transcription factors GABP alpha and -beta to a dyad symmetry element (DSE) of the distal enhancer, which is formed by palindromic binding sites of Ets-like factors.@@@@1@40@@oe@16-12-2010 923469608@GENIA Treebank@formal@@1@S@Introduction of point mutations suppressing GABP binding to the DSE interfered with the induction of the distal enhancer and the entire IL-2 promoter-enhancer, while overexpression of both GABP factors enhanced the IL-2 promoter-enhancer induction.@@@@1@36@@oe@16-12-2010 923469609@GENIA Treebank@formal@@1@S@Overexpression of BXB, a constitutive active version of c-Raf, and of further members of the Ras-Raf-Erk signal cascade exerted an increase of GABP-mediated promoter-enhancer induction.@@@@1@28@@oe@16-12-2010 923469610@GENIA Treebank@formal@@1@S@In conjunction with previously published data on c-Raf-induced phosphorylation of GABP factors (E.Flory, A. Hoffmeyer, U.Smola, U.R.Rapp, and J.T.Bruder, J.Virol.70:2260- 2268, 1996), these results indicate a contribution of GABP factors to the Raf-mediated enhancement of IL-2 induction during T-cell activation.@@@@1@51@@oe@16-12-2010 923472701@GENIA Treebank@formal@@1@S@The product of the murine homolog of the Drosophila extra sex combs gene displays transcriptional repressor activity.@@@@1@18@@oe@16-12-2010 923472702@GENIA Treebank@formal@@1@S@The heterogeneous nuclear ribonucleoprotein K protein represents a novel class of proteins that may act as docking platforms that orchestrate cross-talk among molecules involved in signal transduction and gene expression.@@@@1@31@@oe@16-12-2010 923472703@GENIA Treebank@formal@@1@S@Using a fragment of K protein as bait in the yeast two-hybrid screen, we isolated a cDNA that encodes a protein whose primary structure has extensive similarity to the Drosophila melanogaster extra sex combs (esc) gene product, Esc, a putative silencer of homeotic genes.@@@@1@50@@oe@16-12-2010 923472704@GENIA Treebank@formal@@1@S@The cDNA that we isolated is identical to the cDNA of the recently positionally cloned mouse embryonic ectoderm development gene, eed.@@@@1@23@@oe@16-12-2010 923472705@GENIA Treebank@formal@@1@S@Like Esc, Eed contains six WD-40 repeats in the C-terminal half of the protein and is thought to repress homeotic gene expression during mouse embryogenesis.@@@@1@27@@oe@16-12-2010 923472706@GENIA Treebank@formal@@1@S@Eed binds to K protein through a domain in its N terminus, but interestingly, this domain is not found in the Drosophila Esc.@@@@1@26@@oe@16-12-2010 923472707@GENIA Treebank@formal@@1@S@Gal4-Eed fusion protein represses transcription of a reporter gene driven by a promoter that contains Gal4-binding DNA elements.@@@@1@19@@oe@16-12-2010 923472708@GENIA Treebank@formal@@1@S@Eed also represses transcription when recruited to a target promoter by Gal4-K protein.@@@@1@14@@oe@16-12-2010 923472709@GENIA Treebank@formal@@1@S@Point mutations within the eed gene that are responsible for severe embryonic development abnormalities abolished the transcriptional repressor activity of Eed.@@@@1@22@@oe@16-12-2010 923472710@GENIA Treebank@formal@@1@S@Results of this study suggest that Eed-restricted homeotic gene expression during embryogenesis reflects the action of Eed as a transcriptional repressor.@@@@1@22@@oe@16-12-2010 923472711@GENIA Treebank@formal@@1@S@The Eed-mediated transcriptional effects are likely to reflect the interaction of Eed with multiple molecular partners, including K protein.@@@@1@21@@oe@16-12-2010 923474201@GENIA Treebank@formal@@1@S@Opposite effects of the acute promyelocytic leukemia PML-retinoic acid receptor alpha (RAR alpha) and PLZF-RAR alpha fusion proteins on retinoic acid signalling.@@@@1@25@@oe@16-12-2010 923474202@GENIA Treebank@formal@@1@S@Fusion proteins involving the retinoic acid receptor alpha (RAR alpha) and the PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemias (APLs).@@@@1@31@@oe@16-12-2010 923474203@GENIA Treebank@formal@@1@S@APLs with the PML-RAR alpha or the PLZF-RAR alpha fusion protein are phenotypically indistinguishable except that they differ in their sensitivity to retinoic acid (RA)-induced differentiation: PML-RAR alpha blasts are sensitive to RA and patients enter disease remission after RA treatment, while patients with PLZF-RAR alpha do not.@@@@1@54@@oe@16-12-2010 923474204@GENIA Treebank@formal@@1@S@We here report that (i) like PML-RAR alpha expression, PLZF-RAR alpha expression blocks terminal differentiation of hematopoietic precursor cell lines (U937 and HL-60) in response to different stimuli (vitamin D3, transforming growth factor beta1, and dimethyl sulfoxide); (ii) PML-RAR alpha, but not PLZF-RAR alpha, increases RA sensitivity of hematopoietic precursor cells and restores RA sensitivity of RA-resistant hematopoietic cells; (iii) PML-RAR alpha and PLZF-RAR alpha have similar RA binding affinities; and (iv) PML-RAR alpha enhances the RA response of RA target genes (those for RAR beta, RAR gamma, and transglutaminase type II [TGase]) in vivo, while PLZF-RAR alpha expression has either no effect (RAR beta) or an inhibitory activity (RAR gamma and type II TGase).@@@@1@147@@oe@16-12-2010 923474205@GENIA Treebank@formal@@1@S@These data demonstrate that PML-RAR alpha and PLZF-RAR alpha have similar (inhibitory) effects on RA-independent differentiation and opposite (stimulatory or inhibitory) effects on RA-dependent differentiation and that they behave in vivo as RA-dependent enhancers or inhibitors of RA-responsive genes, respectively.@@@@1@46@@oe@16-12-2010 923474206@GENIA Treebank@formal@@1@S@Their different activities on the RA signalling pathway might underlie the different responses of PML-RAR alpha and PLZF-RAR alpha APLs to RA treatment.@@@@1@24@@oe@16-12-2010 923474207@GENIA Treebank@formal@@1@S@The PLZF-RAR alpha fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein-protein interactions.@@@@1@41@@oe@16-12-2010 923474208@GENIA Treebank@formal@@1@S@Deletion of the PLZF POZ domain partially abrogated the inhibitory effect of PLZF-RAR alpha on RA-induced differentiation and on RA-mediated type II TGase up-regulation, suggesting that POZ-mediated protein interactions might be responsible for the inhibitory transcriptional activities of PLZF-RAR alpha.@@@@1@42@@oe@16-12-2010 923644801@GENIA Treebank@formal@@1@S@Glucocorticoid receptor regulates expression of L-selectin and CD11/CD18 on human neutrophils [see comments]@@@@1@15@@oe@16-12-2010 923644802@GENIA Treebank@formal@@1@S@BACKGROUND: Recent studies have raised the hypothesis that glucocorticoids could diminish the ability of endothelial cells to direct leukocyte traffic into inflamed tissues by inhibiting expression of the adhesion molecules endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1.@@@@1@39@@oe@16-12-2010 923644803@GENIA Treebank@formal@@1@S@The aim of the present study was to investigate whether glucocorticoids also regulate the expression of L-selectin and CD11/CD18 integrins on human neutrophil granulocytes.@@@@1@25@@oe@16-12-2010 923644804@GENIA Treebank@formal@@1@S@METHODS AND RESULTS: Incubation of human whole blood with platelet-activating factor (PAF, 1 mumol/L) evoked downregulation of L-selectin and upregulation of CD11/CD18 adhesion receptors on neutrophils as measured by flow cytometry.@@@@1@36@@oe@16-12-2010 923644805@GENIA Treebank@formal@@1@S@While dexamethasone (0.1 nmol/L to 100 mumol/L) did not affect expression of adhesion molecules on resting neutrophils, it attenuated the PAF-induced changes in L-selectin and CD18 expression in a time- and concentration-dependent fashion with IC50 values of 31 and 13 nmol/L, respectively.@@@@1@47@@oe@16-12-2010 923644806@GENIA Treebank@formal@@1@S@These effects of dexamethasone were completely aborted by RU-486 (10 mumol/L), which blocks transcriptional activation of the glucocorticoid receptor, and by the protein synthesis inhibitor cycloheximide (35.5 mumol/L).@@@@1@35@@oe@16-12-2010 923644807@GENIA Treebank@formal@@1@S@Dexamethasone, up to a concentration of 1 mumol/L, neither affected significantly the release of granule enzymes nor interfered with PAF binding to its membrane receptors.@@@@1@28@@oe@16-12-2010 923644808@GENIA Treebank@formal@@1@S@CONCLUSIONS: Our results show that glucocorticoids at clinically relevant concentrations exert specific actions on expression of adhesion molecules on activated neutrophils, which are mediated through ligation of glucocorticoid receptors and induction of protein synthesis, and suggest a novel mechanism by which anti-inflammatory corticosteroids may inhibit leukocyte accumulation.@@@@1@51@@oe@16-12-2010 923771601@GENIA Treebank@formal@@1@S@Induction of human immunodeficiency virus type 1 expression in monocytic cells by Cryptococcus neoformans and Candida albicans.@@@@1@18@@oe@16-12-2010 923771602@GENIA Treebank@formal@@1@S@Because candidiasis and cryptococcosis are common in human immunodeficiency virus (HIV)-infected persons, the effect of Cryptococcus neoformans and Candida albicans on HIV expression in monocytic cells was examined.@@@@1@33@@oe@16-12-2010 923771603@GENIA Treebank@formal@@1@S@Stimulation of the latently HIV-infected myelomonocytic cell line OM-10.1 with C. neoformans and C. albicans in the presence of pooled human serum caused a ratio-dependent increase in HIV production.@@@@1@30@@oe@16-12-2010 923771604@GENIA Treebank@formal@@1@S@Induction of HIV by C. neoformans was enhanced by anti-capsular antibody, while induction by both organisms was inhibited by anti-TNF-alpha antibody.@@@@1@23@@oe@16-12-2010 923771605@GENIA Treebank@formal@@1@S@In THP-1 cells transfected with HIV plasmid constructs, both organisms induced transcription from the HIV long terminal repeat that was dependent on intact NF-kappaB binding sequences.@@@@1@28@@oe@16-12-2010 923771606@GENIA Treebank@formal@@1@S@Thus, C. neoformans and C. albicans enhance HIV expression in monocytic cells through a TNF-alpha- and NF-kappaB-dependent mechanism.@@@@1@20@@oe@16-12-2010 923771607@GENIA Treebank@formal@@1@S@In HIV-infected patients, such enhancement may further impair host immunity and could accelerate the course of HIV disease.@@@@1@20@@oe@16-12-2010 923775901@GENIA Treebank@formal@@1@S@A human homologue of the Drosophila Toll protein signals activation of adaptive immunity [see comments]@@@@1@17@@oe@16-12-2010 923775902@GENIA Treebank@formal@@1@S@Induction of the adaptive immune response depends on the expression of co-stimulatory molecules and cytokines by antigen-presenting cells.@@@@1@19@@oe@16-12-2010 923775903@GENIA Treebank@formal@@1@S@The mechanisms that control the initial induction of these signals upon infection are poorly understood.@@@@1@16@@oe@16-12-2010 923775904@GENIA Treebank@formal@@1@S@It has been proposed that their expression is controlled by the non-clonal, or innate, component of immunity that preceded in evolution the development of an adaptive immune system in vertebrates.@@@@1@33@@oe@16-12-2010 923775905@GENIA Treebank@formal@@1@S@We report here the cloning and characterization of a human homologue of the Drosophila toll protein (Toll) which has been shown to induce the innate immune response in adult Drosophila.@@@@1@33@@oe@16-12-2010 923775906@GENIA Treebank@formal@@1@S@Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor.@@@@1@45@@oe@16-12-2010 923775907@GENIA Treebank@formal@@1@S@Both Drosophila Toll and the IL-1 receptor are known to signal through the NF-kappaB pathway.@@@@1@16@@oe@16-12-2010 923775908@GENIA Treebank@formal@@1@S@We show that a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-kappaB and the expression of NF-kappaB-controlled genes for the inflammatory cytokines IL-1, IL-6 and IL-8, as well as the expression of the co-stimulatory molecule B7.1, which is required for the activation of naive T cells.@@@@1@59@@oe@16-12-2010 923792901@GENIA Treebank@formal@@1@S@Regulation of B-cell commitment to plasma cells or to memory B cells.@@@@1@13@@oe@16-12-2010 923792902@GENIA Treebank@formal@@1@S@During humoral immune responses, B-lymphocyte activation is followed by differentiation along either the plasma cell pathway or the memory B-cell pathway.@@@@1@23@@oe@16-12-2010 923792903@GENIA Treebank@formal@@1@S@Recent studies suggest that CD40-CD40 ligand, OX-OX40 ligand, a group of cytokines and intracellular transcriptional factors may all contribute to B-lymphocyte differentiation control.@@@@1@26@@oe@16-12-2010 924243101@GENIA Treebank@formal@@1@S@Bcl-2 protein inhibits bufalin-induced apoptosis through inhibition of mitogen-activated protein kinase activation in human leukemia U937 cells.@@@@1@18@@oe@16-12-2010 924243102@GENIA Treebank@formal@@1@S@In a previous study, we demonstrated that bufalin, which is an active principle of Chinese medicine, chan'su, caused apoptosis in human leukemia U937 cells by anomalous activation of mitogen-activated protein kinase (MAPK) via the signaling pathway of Ras, Raf-1, and MAPK kinase-1.@@@@1@51@@oe@16-12-2010 924243103@GENIA Treebank@formal@@1@S@Here, we report the effect of overexpression of bcl-2 in U937 cells on the signaling pathway of apoptosis that is induced by bufalin.@@@@1@25@@oe@16-12-2010 924243104@GENIA Treebank@formal@@1@S@The results indicated that the apoptosis induced by bufalin in U937 cells was significantly inhibited by overexpression of the Bcl-2 protein.@@@@1@22@@oe@16-12-2010 924243105@GENIA Treebank@formal@@1@S@No significant difference was detected in the activation of MAPK kinase-1 that is induced by bufalin in wild-type or Bcl-2-overexpressed U937 cells; however, the activation of MAPK by bufalin was significantly attenuated in the cells overexpressing Bcl-2.@@@@1@40@@oe@16-12-2010 924243106@GENIA Treebank@formal@@1@S@Bufalin treatment activated activator protein-1 transcriptional activity; however, this activation was decreased to 40% in bcl-2-overexpressed U937 cells.@@@@1@22@@oe@16-12-2010 924243107@GENIA Treebank@formal@@1@S@These results indicate that Bcl-2 acts downstream of MAPK kinase-1 but upstream of MAPK and suggest that, in the signaling pathway of the apoptotic process induced by bufalin, the transcriptional activity of activator protein-1 may be down-regulated through the inhibition of MAPK activity by Bcl-2.@@@@1@48@@oe@16-12-2010 924256401@GENIA Treebank@formal@@1@S@A shortened life span of EKLF-/- adult erythrocytes, due to a deficiency of beta-globin chains, is ameliorated by human gamma-globin chains.@@@@1@24@@oe@16-12-2010 924256402@GENIA Treebank@formal@@1@S@Using homologous recombination, both EKLF alleles in murine embryonic stem (ES) cells were inactivated.@@@@1@18@@oe@16-12-2010 924256403@GENIA Treebank@formal@@1@S@These EKLF-/- ES cells were capable of undergoing in vitro differentiation to form definitive erythroid colonies that were similar in size and number to those formed by wild-type ES cells.@@@@1@31@@oe@16-12-2010 924256404@GENIA Treebank@formal@@1@S@However, the EKLF-/- colonies were poorly hemoglobinized and enucleated erythrocytes in these colonies contained numerous Heinz bodies.@@@@1@19@@oe@16-12-2010 924256405@GENIA Treebank@formal@@1@S@Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses revealed that adult and embryonic globin genes were appropriately regulated, with the exception of beta h1-globin, which continued to be expressed at a very low level.@@@@1@37@@oe@16-12-2010 924256406@GENIA Treebank@formal@@1@S@The ratio of adult beta-globin/alpha-globin mRNA in the mutant ES cells was 1/15 of that in wild-type ES cells.@@@@1@20@@oe@16-12-2010 924256407@GENIA Treebank@formal@@1@S@When the EKLF-/- cells were injected into blastocysts, they did not contribute at a detectable level to the mature erythrocyte compartment of the chimeric animals, based on analysis of glucose phosphate isomerase-1 (GPI-1) isozymes and hemoglobins that distinguish ES cell-derived erythrocytes from host blastocyst-derived erythrocytes.@@@@1@50@@oe@16-12-2010 924256408@GENIA Treebank@formal@@1@S@In contrast, semiquantitative RT-PCR analysis of RNA from reticulocytes of the same chimeric animals suggested that the ES cell-derived reticulocytes were present at a level of 6% to 8%.@@@@1@33@@oe@16-12-2010 924256409@GENIA Treebank@formal@@1@S@This indicated that the EKLF-/- erythrocytes in adult animals must be short-lived, apparently due to the imbalance of beta- versus alpha-globin chains, leading to the precipitation of excess alpha-globin chains to form Heinz bodies.@@@@1@37@@oe@16-12-2010 924256410@GENIA Treebank@formal@@1@S@Consistent with this hypothesis, the short life span was ameliorated by introduction into the EKLF-/- ES cells of a human LCR/gamma-globin gene, as evidenced by the presence of ES cell-derived reticulocytes as well as mature erythrocytes in the blood of the chimeric animals.@@@@1@46@@oe@16-12-2010 924374801@GENIA Treebank@formal@@1@S@Induction of nuclear factor kappa B/Rel nuclear activity in human peripheral blood T lymphocytes by anti-HLA class I monoclonal antibodies.@@@@1@21@@oe@16-12-2010 924374802@GENIA Treebank@formal@@1@S@Monoclonal antibodies against either monomorphic or polymorphic determinants of class I antigen induced in PBMC and highly purified T lymphocytes the nuclear activity of NF-kappa B/Rel complexes.@@@@1@28@@oe@16-12-2010 924374803@GENIA Treebank@formal@@1@S@These included both p50/p50 and p50/p65 dimers, recognized by specific antibodies in EMSA.@@@@1@15@@oe@16-12-2010 924374804@GENIA Treebank@formal@@1@S@The induced complexes were detectable in extracts of cells incubated with anti-class I monoclonal antibody (mAb) for 1.5 h; the induction was maximal at 5 h, persistent at 16 h and no longer observed at 40 h.@@@@1@42@@oe@16-12-2010 924374805@GENIA Treebank@formal@@1@S@The mAb failed to induce NF-kappa B/Rel nuclear activity in cells incubated in the presence of 3,4-dichloroisocoumarin, an inhibitor of I kappa B-alpha degradation.@@@@1@26@@oe@16-12-2010 924374806@GENIA Treebank@formal@@1@S@Together, these results suggest that class I triggering can induce the activity of NF-kappa B/Rel nuclear activity in peripheral blood T lymphocytes, thereby modulating the expression of genes regulated by these transcription factors.@@@@1@36@@oe@16-12-2010 924756701@GENIA Treebank@formal@@1@S@Cyclosporin A interferes with the inducible degradation of NF-kappa B inhibitors, but not with the processing of p105/NF-kappa B1 in T cells.@@@@1@24@@oe@16-12-2010 924756702@GENIA Treebank@formal@@1@S@The transcription factor NF-kappa B controls the induction of numerous cytokine promoters during the activation of T lymphocytes.@@@@1@19@@oe@16-12-2010 924756703@GENIA Treebank@formal@@1@S@Inhibition of T cell activation by the immunosuppressants cyclosporin A (CsA) and FK506 exerts a suppressive effect on the induction of these NF-kappa B-controlled cytokine promoters.@@@@1@29@@oe@16-12-2010 924756704@GENIA Treebank@formal@@1@S@We show for human Jurkat T leukemia cells, as well as human and mouse primary T lymphocytes, that this inhibitory effect is accompanied by an impaired nuclear translocation of the Rel proteins c-Rel, RelA/p65 and NF-kappa B1/p50, whereas the nuclear appearance of RelB remains unaffected.@@@@1@50@@oe@16-12-2010 924756705@GENIA Treebank@formal@@1@S@CsA does not interfere with the synthesis of Rel proteins, but prevents the inducible degradation of cytosolic NF-kappa B inhibitors I kappa B alpha and I kappa B beta upon T cell activation.@@@@1@35@@oe@16-12-2010 924756706@GENIA Treebank@formal@@1@S@CsA neither inhibits the processing of the NF-kappa B1 precursor p105 to p50, nor does it "stabilize" the C-terminal portion of p105, I kappa B gamma, which is degraded during p105 processing to mature p50.@@@@1@41@@oe@16-12-2010 924756707@GENIA Treebank@formal@@1@S@These results indicate that CsA interferes with a specific event in the signal-induced degradation of I kappa B alpha and I kappa B beta, but does not affect the processing of NF-kappa B1/p105 to p50.@@@@1@37@@oe@16-12-2010 925211701@GENIA Treebank@formal@@1@S@EBF and E47 collaborate to induce expression of the endogenous immunoglobulin surrogate light chain genes.@@@@1@16@@oe@16-12-2010 925211702@GENIA Treebank@formal@@1@S@Early B cell factor (EBF) and E47 participate in the transcriptional control of early B lymphocyte differentiation.@@@@1@20@@oe@16-12-2010 925211703@GENIA Treebank@formal@@1@S@With the aim of identifying genetic targets for these transcription factors, we stably transfected cDNAs encoding EBF or a covalent homodimer of E47, individually or together, into immature hematopoietic Ba/F3 cells, which lack both factors.@@@@1@40@@oe@16-12-2010 925211704@GENIA Treebank@formal@@1@S@In combination, EBF and E47 induce efficient expression of the endogenous immunoglobulin surrogate light chain genes, lambda5 and VpreB, whereas other pre-B cell-specific genes remain silent.@@@@1@30@@oe@16-12-2010 925211705@GENIA Treebank@formal@@1@S@Multiple functionally important EBF and E47 binding sites were identified in the lambda5 promoter/enhancer region, indicating that lambda5 is a direct genetic target for these transcription factors.@@@@1@29@@oe@16-12-2010 925211706@GENIA Treebank@formal@@1@S@Taken together, these data suggest that EBF and E47 synergize to activate expression of a subset of genes that define an early stage of the B cell lineage.@@@@1@30@@oe@16-12-2010 925623401@GENIA Treebank@formal@@1@S@Nuclear levels of NF-kappaB correlate with syncytium-forming capacity of 8e51 cells, expressing a defective HIV virus.@@@@1@18@@oe@16-12-2010 925623402@GENIA Treebank@formal@@1@S@The double NF-kappaB site identified in the LTR of the human immunodeficiency virus-1 (HIV-1) has been demonstrated to be necessary for efficient viral transcription.@@@@1@27@@oe@16-12-2010 925623403@GENIA Treebank@formal@@1@S@In this report we present the characterisation of NF-kappaB subunits engaged in complexes binding to the HIV-1 NF-kappaB site in human 8e51 T-cells, that harbour a defective HIV-1.@@@@1@30@@oe@16-12-2010 925623404@GENIA Treebank@formal@@1@S@At least four different specific NF-kappaB complexes are present in the nucleus of these cells.@@@@1@16@@oe@16-12-2010 925623405@GENIA Treebank@formal@@1@S@With the use of specific antibodies we have determined the composition of each complex using electrophoretic mobility shift assays.@@@@1@20@@oe@16-12-2010 925623406@GENIA Treebank@formal@@1@S@The results show the presence of several NF-kappaB family members, with the transactivating RelA being engaged in multiple complexes.@@@@1@21@@oe@16-12-2010 925623407@GENIA Treebank@formal@@1@S@The importance of NF-kappaB complexes in viral functions has been established comparing the level of NF-kappaB DNA-binding complexes with syncytia-forming activity of 8e51 cells.@@@@1@25@@oe@16-12-2010 925623408@GENIA Treebank@formal@@1@S@In fact, 8e51 cells that had almost lost their syncytia-forming capacity were found to contain at least 10 times less active NF-kappaB DNA-binding complex than the actively fusing cells.@@@@1@31@@oe@16-12-2010 925623409@GENIA Treebank@formal@@1@S@The correlation is specific as the level of at least three other transcription factors did not change.@@@@1@18@@oe@16-12-2010 925784301@GENIA Treebank@formal@@1@S@Differential interaction of nuclear factors with the leukocyte-specific pp52 promoter in B and T cells.@@@@1@16@@oe@16-12-2010 925784302@GENIA Treebank@formal@@1@S@The leukocyte-specific, cytoskeleton-binding pp52 (LSP-1, WP-34) protein is widely expressed in multiple leukocyte lineages, including B and T lymphocytes, granulocytes, and macrophages.@@@@1@30@@oe@16-12-2010 925784303@GENIA Treebank@formal@@1@S@We previously detected a tissue-specific promoter preceding the exon encoding the N terminus of the pp52 leukocyte protein.@@@@1@19@@oe@16-12-2010 925784304@GENIA Treebank@formal@@1@S@Here we describe the functional characterization of this promoter and identification of the factors in B and T cells that regulate its activity.@@@@1@24@@oe@16-12-2010 925784305@GENIA Treebank@formal@@1@S@The pp52 promoter contains an initiator specifying the unique 5' terminus of pp52 mRNA, tandem pairs of Ets and SP1 motifs, and a lone C/EBP motif.@@@@1@29@@oe@16-12-2010 925784306@GENIA Treebank@formal@@1@S@All these motifs are essential and collectively control transcriptional activity.@@@@1@11@@oe@16-12-2010 925784307@GENIA Treebank@formal@@1@S@DNA binding studies and Ab supershift assays revealed that different combinations of factors interact with these motifs in B cells vs T cells.@@@@1@24@@oe@16-12-2010 925784308@GENIA Treebank@formal@@1@S@The Ets motifs are preferentially bound by PU-1 in B cell extracts from all stages of development, whereas a different Ets family member reacts with these motifs in T cell extracts.@@@@1@33@@oe@16-12-2010 925784309@GENIA Treebank@formal@@1@S@The C/EBP motif is bound by Ig/EBP-1 in pre-B cell and T cell extracts, but is replaced by nuclear factor-IL-6beta or a nuclear factor-IL-6beta-Ig/EBP-1 heterodimer in plasmacytoma cell extracts.@@@@1@31@@oe@16-12-2010 925784310@GENIA Treebank@formal@@1@S@Despite its reported role as a negative regulator of transcription, Ig/EBP-1 appears to exert a stimulatory effect on this promoter.@@@@1@22@@oe@16-12-2010 925784311@GENIA Treebank@formal@@1@S@These findings reveal the features controlling the pp52 promoter in B and T cells and provide the foundation for determining the regulation of this promoter in other leukocyte lineages.@@@@1@30@@oe@16-12-2010 925931601@GENIA Treebank@formal@@1@S@Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo.@@@@1@14@@oe@16-12-2010 925931602@GENIA Treebank@formal@@1@S@Some of the most potent antiinflammatory and immunosuppressive agents are synthetic glucocorticoids.@@@@1@13@@oe@16-12-2010 925931603@GENIA Treebank@formal@@1@S@However, major side effects severely limit their therapeutic use.@@@@1@11@@oe@16-12-2010 925931604@GENIA Treebank@formal@@1@S@The development of improved glucocorticoid-based drugs will require the separation of beneficial from deleterious effects.@@@@1@16@@oe@16-12-2010 925931605@GENIA Treebank@formal@@1@S@One possibility toward this goal is to try to dissociate two main activities of glucocorticoids, i.e. transactivation and transrepression.@@@@1@21@@oe@16-12-2010 925931606@GENIA Treebank@formal@@1@S@Screening of a library of compounds using transactivation and AP-1 transrepression models in transiently transfected cells identified dissociated glucocorticoids, which exert strong AP-1 inhibition but little or no transactivation.@@@@1@31@@oe@16-12-2010 925931607@GENIA Treebank@formal@@1@S@Importantly, despite high ligand binding affinity, the prototypic dissociated compound, RU24858, acted as a weak agonist and did not efficiently antagonize dexamethasone-induced transcription in transfected cells.@@@@1@31@@oe@16-12-2010 925931608@GENIA Treebank@formal@@1@S@Similar results were obtained in hepatic HTC cells for the transactivation of the endogenous tyrosine amino transferase gene (TAT), which encodes one of the enzymes involved in the glucocorticoid-dependent stimulation of neoglucogenesis.@@@@1@36@@oe@16-12-2010 925931609@GENIA Treebank@formal@@1@S@To investigate whether dissociated glucocorticoids retained the antiinflammatory and immunosuppressive potential of classic glucocorticoids, several in vitro and in vivo models were used.@@@@1@25@@oe@16-12-2010 925931610@GENIA Treebank@formal@@1@S@Indeed, secretion of the proinflammatory lymphokine interleukin-1beta was severely inhibited by dissociated glucocorticoids in human monocytic THP 1 cells.@@@@1@21@@oe@16-12-2010 925931611@GENIA Treebank@formal@@1@S@Moreover, in two in vivo models, these compounds exerted an antiinflammatory and immunosuppressive activity as potent as that of the classic glucocorticoid prednisolone.@@@@1@26@@oe@16-12-2010 925931612@GENIA Treebank@formal@@1@S@These results may lead to an improvement of antiinflammatory and immunosuppressive therapies and provide a novel concept for drug discovery.@@@@1@21@@oe@16-12-2010 926114601@GENIA Treebank@formal@@1@S@Critical cytoplasmic domains of human interleukin-9 receptor alpha chain in interleukin-9-mediated cell proliferation and signal transduction.@@@@1@17@@oe@16-12-2010 926114602@GENIA Treebank@formal@@1@S@Interleukin-9 receptor (IL-9R) complex consists of a ligand-specific alpha chain and IL-2R gamma chain.@@@@1@17@@oe@16-12-2010 926114603@GENIA Treebank@formal@@1@S@In this study, two regions in the cytoplasmic domain of human IL-9Ralpha were found to be important for IL-9-mediated cell growth.@@@@1@23@@oe@16-12-2010 926114604@GENIA Treebank@formal@@1@S@A membrane-proximal region that contains the BOX1 consensus sequence is required for IL-9-induced cell proliferation and tyrosine phosphorylation of Janus kinases (JAKs).@@@@1@25@@oe@16-12-2010 926114605@GENIA Treebank@formal@@1@S@Deletion of this region or internal deletion of the BOX1 motif abrogated IL-9-induced cell proliferation and signal transduction.@@@@1@19@@oe@16-12-2010 926114606@GENIA Treebank@formal@@1@S@However, substitution of the Pro-X-Pro in the BOX1 motif with Ala-X-Ala failed to abolish IL-9-induced cell proliferation but decreased IL-9-mediated tyrosine phosphorylation of JAK kinases, insulin receptor substrate-2, and signal transducer and activator of transcription 3 (STAT3) and expression of c-myc and junB.@@@@1@49@@oe@16-12-2010 926114607@GENIA Treebank@formal@@1@S@Another important region is downstream of the BOX1 motif and contains a STAT3 binding motif YLPQ.@@@@1@17@@oe@16-12-2010 926114608@GENIA Treebank@formal@@1@S@Deletion of this region significantly impaired IL-9-induced cell growth, activation of JAK kinases, insulin receptor substrate-2, and STAT3 and expression of early response genes.@@@@1@28@@oe@16-12-2010 926114609@GENIA Treebank@formal@@1@S@A point mutation changing YLPQ into YLPA greatly reduced IL-9-induced activation of STAT3 and expression of c-myc but did not affect cell proliferation.@@@@1@24@@oe@16-12-2010 926114610@GENIA Treebank@formal@@1@S@These results suggest that cooperation or cross-talk of signaling molecules associated with different domains of IL-9Ralpha other than STAT3 is essential for IL-9-mediated cell growth.@@@@1@26@@oe@16-12-2010 926118101@GENIA Treebank@formal@@1@S@Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene.@@@@1@21@@oe@16-12-2010 926118102@GENIA Treebank@formal@@1@S@Interleukin-5 (IL-5), which is produced by CD4(+) T helper 2 (Th2) cells, but not by Th1 cells, plays a key role in the development of eosinophilia in asthma.@@@@1@36@@oe@16-12-2010 926118103@GENIA Treebank@formal@@1@S@Despite increasing evidence that the outcome of many diseases is determined by the ratio of the two subsets of CD4(+) T helper cells, Th1 and Th2, the molecular basis for Th1- and Th2- specific gene expression remains to be elucidated.@@@@1@42@@oe@16-12-2010 926118104@GENIA Treebank@formal@@1@S@We previously established a critical role for the transcription factor GATA-3 in IL-5 promoter activation in EL-4 cells, which express both Th1- and Th2-type cytokines.@@@@1@27@@oe@16-12-2010 926118105@GENIA Treebank@formal@@1@S@Our studies reported here demonstrate that GATA-3 is critical for expression of the IL-5 gene in bona fide Th2 cells.@@@@1@21@@oe@16-12-2010 926118106@GENIA Treebank@formal@@1@S@Whereas mutations in the GATA-3 site abolished antigen- or cAMP- stimulated IL-5 promoter activation in Th2 cells, ectopic expression of GATA-3 in Th1 cells or in a non-lymphoid, non-IL-5-producing cell line activated the IL-5 promoter.@@@@1@37@@oe@16-12-2010 926118107@GENIA Treebank@formal@@1@S@During the differentiation of naive CD4(+) T cells isolated from T cell receptor transgenic mice, GATA-3 gene expression was up-regulated in developing Th2 cells, but was down-regulated in Th1 cells, and antigen- or cAMP-activated Th2 cells (but not Th1 cells) expressed the GATA-3 protein.@@@@1@50@@oe@16-12-2010 926118108@GENIA Treebank@formal@@1@S@Thus, GATA-3 may play an important role in the balance between Th1 and Th2 subsets in immune responses.@@@@1@20@@oe@16-12-2010 926118109@GENIA Treebank@formal@@1@S@Inhibition of GATA-3 activity has therapeutic potential in the treatment of asthma and other hypereosinophilic diseases.@@@@1@17@@oe@16-12-2010 926136701@GENIA Treebank@formal@@1@S@Inhibition of human immunodeficiency virus type 1 replication in vitro by a novel combination of anti-Tat single-chain intrabodies and NF-kappa B antagonists.@@@@1@23@@oe@16-12-2010 926136702@GENIA Treebank@formal@@1@S@Human immunodeficiency virus type 1 (HIV-1) Tat, an early regulatory protein that is critical for viral gene expression and replication, transactivates the HIV-1 long terminal repeat (LTR) via its binding to the transactivation response element (TAR) and, along with other cellular factors, increases viral transcription initiation and elongation.@@@@1@59@@oe@16-12-2010 926136703@GENIA Treebank@formal@@1@S@Tat also superactivates the HIV-1 promoter through a TAR-independent mechanism, including tumor necrosis factor alpha-induced and protein kinase C (PKC)-dependent activation of NF-kappa B, and inhibitors of Tat and NF-kappa B cooperatively down-regulate this Tat-mediated LTR superactivation.@@@@1@43@@oe@16-12-2010 926136704@GENIA Treebank@formal@@1@S@In this study, a combined pharmacologic and genetic strategy using two PKC (NF-kappa B) inhibitors, pentoxifylline (PTX) and Go-6976, and a stably expressed anti-Tat single-chain intracellular antibody (sFv intrabody) was employed to obtain cooperative inhibition of both HIV-1 LTR-driven gene expression and HIV-1 replication.@@@@1@54@@oe@16-12-2010 926136705@GENIA Treebank@formal@@1@S@Treatment of cells with PTX and Go-6976 resulted in cooperative inhibition of both HIV-1 LTR-driven gene expression and HIV-1 replication.@@@@1@21@@oe@16-12-2010 926136706@GENIA Treebank@formal@@1@S@In addition, the combined use of anti-Tat sFv intrabodies and the two NF-kappa B inhibitors retained the virus in the latent state for as long as 45 days.@@@@1@30@@oe@16-12-2010 926136707@GENIA Treebank@formal@@1@S@The combined treatment resulted in more durable inhibition of HIV-1 replication than was seen with the NF-kappa B inhibitors alone or the anti-Tat sFv intrabodies alone.@@@@1@27@@oe@16-12-2010 926136708@GENIA Treebank@formal@@1@S@Together, these results suggest that in future clinical gene therapy trials, a combined pharmacologic and genetic strategy like the one reported here may improve the survival of transduced cells and prolong clinical benefit.@@@@1@36@@oe@16-12-2010 926137501@GENIA Treebank@formal@@1@S@Activation domain requirements for disruption of Epstein-Barr virus latency by ZEBRA.@@@@1@12@@oe@16-12-2010 926137502@GENIA Treebank@formal@@1@S@Latent infection of B lymphocytes by Epstein-Barr virus (EBV) can be disrupted by expression of the EBV ZEBRA protein.@@@@1@22@@oe@16-12-2010 926137503@GENIA Treebank@formal@@1@S@ZEBRA, a transcriptional activator, initiates the EBV lytic cascade by activating viral gene expression.@@@@1@17@@oe@16-12-2010 926137504@GENIA Treebank@formal@@1@S@ZEBRA is also indispensable for viral replication and binds directly to the EBV lytic origin of replication.@@@@1@18@@oe@16-12-2010 926137505@GENIA Treebank@formal@@1@S@The studies described herein demonstrate that the activation domain.@@@@1@10@@oe@16-12-2010 926137506@GENIA Treebank@formal@@1@S@ZEBRA activation can be replaced by a heterologous acidic, proline-rich, or glutamine-rich activation domain.@@@@1@17@@oe@16-12-2010 926137507@GENIA Treebank@formal@@1@S@ZEBRA activation domain swap constructs retain ZEBRA's native abilities to activate specific EBV promoters, to disrupt EBV latency, and to stimulate replication at the EBV lytic origin.@@@@1@31@@oe@16-12-2010 926137508@GENIA Treebank@formal@@1@S@Additional work, employing sequential and internal deletions of ZEBRA's N-terminal activation domain, indicates that its separate activities are not attributable to specific subdomains but are spread throughout its N terminus and therefore cannot be inactivated by deleting localized regions.@@@@1@44@@oe@16-12-2010 926572701@GENIA Treebank@formal@@1@S@Transcription factors in immune-mediated disease.@@@@1@6@@oe@16-12-2010 926572702@GENIA Treebank@formal@@1@S@A large amount of detailed information about the intracellular proteins regulating NF-kappa B activation and the cellular response to NF-kappa B activation has emerged recently.@@@@1@26@@oe@16-12-2010 926572703@GENIA Treebank@formal@@1@S@Several small molecules, an antisense oligonucleotide, and gene therapeutic agents that inhibit NF-kappa b activation have been described.@@@@1@21@@oe@16-12-2010 926572704@GENIA Treebank@formal@@1@S@Despite this, there are still significant gaps in our understanding of this process and its consequences.@@@@1@18@@oe@16-12-2010 926572705@GENIA Treebank@formal@@1@S@In contrast, the characterization of transcription factors selectively regulating cytokine production by CD4+ T cell subsets is at a very early stage.@@@@1@24@@oe@16-12-2010 926572706@GENIA Treebank@formal@@1@S@Three interacting proteins have recently been shown to contribute to subset-restricted expression of the IL-4 gene.@@@@1@17@@oe@16-12-2010 926572707@GENIA Treebank@formal@@1@S@There are other elements regulating IL-4 gene expression, however, and the relative importance of these recently identified proteins has yet to be determined.@@@@1@26@@oe@16-12-2010 927135201@GENIA Treebank@formal@@1@S@CholecystokininB receptor from human Jurkat lymphoblastic T cells is involved in activator protein-1-responsive gene activation.@@@@1@16@@oe@16-12-2010 927135202@GENIA Treebank@formal@@1@S@The aim of this study was to analyze the role of cholecystokinin (CCK(B)) receptor in human lymphoblastic Jurkat T cells.@@@@1@23@@oe@16-12-2010 927135203@GENIA Treebank@formal@@1@S@We investigated the trophic effect resulting from activation of such a receptor by using the reporter gene strategy.@@@@1@19@@oe@16-12-2010 927135204@GENIA Treebank@formal@@1@S@For this purpose, we transiently transfected Jurkat T cells with the reporter plasmid p[(TRE)3-tk-Luc] and found that CCK-8 was able to dose-dependently induce luciferase expression related to activator protein-1 (AP-1) activation with a maximal response identical to that obtained with compounds known to activate AP-1 complex (quantitatively, the same level of induction was obtained with 1 nM 12-O-tetradecanoylphorbol-13-acetate, 100 microM diacylglycerol, or 4 nM epidermal growth factor).@@@@1@77@@oe@16-12-2010 927135205@GENIA Treebank@formal@@1@S@The involvement of the CCK(B) receptor in such a stimulation was demonstrated by the inhibiting effect of the selective CCK(B) receptor antagonist PD-135,158.@@@@1@24@@oe@16-12-2010 927135206@GENIA Treebank@formal@@1@S@This effect was confirmed in COS-7 cells transfected with the cDNA of CCK(B) receptor cloned from Jurkat T cells.@@@@1@20@@oe@16-12-2010 927135207@GENIA Treebank@formal@@1@S@To better understand the AP-1-dependent luciferase expression in Jurkat T cells, we tested two specific inhibitors of serine/threonine phosphatases-1 and -2A: okadaic acid and calyculin A.@@@@1@29@@oe@16-12-2010 927135208@GENIA Treebank@formal@@1@S@These compounds strongly increased the phorbol-12-myristate-13-acetate response, whereas we have not observed a contribution of phosphatase inhibitors on a CCK-8-induced luciferase activity.@@@@1@24@@oe@16-12-2010 927135209@GENIA Treebank@formal@@1@S@To confirm that CCK(B) receptors are involved in AP-1 response, we investigated the CCK-8 effect on interleukin-2 expression, a natural endogenous gene regulated by several factors, including AP-1.@@@@1@32@@oe@16-12-2010 927135210@GENIA Treebank@formal@@1@S@In Jurkat T cells activated by phorbol-12-myristate-13-acetate and phytohemagglutinin, CCK-8 induced IL-2 expression.@@@@1@15@@oe@16-12-2010 927135211@GENIA Treebank@formal@@1@S@This induction was abolished by PD-135,158.@@@@1@7@@oe@16-12-2010 927135212@GENIA Treebank@formal@@1@S@Our results indicate that CCK-8 exerts a trophic effect in Jurkat T cells through stimulation of CCK(B) receptors by modulation of expression of AP-1-regulated genes.@@@@1@26@@oe@16-12-2010 927158801@GENIA Treebank@formal@@1@S@Epstein-Barr virus binding to CD21 activates the initial viral promoter via NF-kappaB induction.@@@@1@14@@oe@16-12-2010 927158802@GENIA Treebank@formal@@1@S@Epstein-Barr virus (EBV), an oncogenic human herpesvirus, binds to and infects normal human B lymphocytes via CD21, the CR2 complement receptor.@@@@1@27@@oe@16-12-2010 927158803@GENIA Treebank@formal@@1@S@Studies of the mechanisms that enable EBV to infect nonactivated, noncycling B cells provide compelling evidence for a sequence of events in which EBV binding to CD21 on purified resting human B cells rapidly activates the NF-kappaB transcription factor, which, in turn, binds to and mediates transcriptional activation of Wp, the initial viral latent gene promoter.@@@@1@62@@oe@16-12-2010 927158804@GENIA Treebank@formal@@1@S@Thus, EBV binding to its cellular receptor on resting B cells triggers an NF-kappaB-dependent intracellular signaling pathway which is required for infection.@@@@1@24@@oe@16-12-2010 927647101@GENIA Treebank@formal@@1@S@Activation of transcription factor NF-kappa B by phagocytic stimuli in human neutrophils.@@@@1@13@@oe@16-12-2010 927647102@GENIA Treebank@formal@@1@S@Phagocytosis represents an important physiological trigger for the inducible expression of several genes in human neutrophils.@@@@1@17@@oe@16-12-2010 927647103@GENIA Treebank@formal@@1@S@Here, we report that a DNA-binding activity primarily consisting of the classical NF-kappa B heterodimer, p50/RelA, is induced in phagocytosing neutrophils.@@@@1@25@@oe@16-12-2010 927647104@GENIA Treebank@formal@@1@S@Under these conditions, NF-kappa B activation was found to be a rapid and transient response, reaching a maximum by 10-15 min, and returning to near-basal levels by 30 min.@@@@1@33@@oe@16-12-2010 927647105@GENIA Treebank@formal@@1@S@In neutrophils undergoing the phagocytosis of opsonized yeasts, the onset of NF-kappa B activation was paralleled by a decline in immunoreactive I kappa B-alpha protein levels, and the cellular I kappa B-alpha pool was replenished by 30 min, in agreement with our gel shift data.@@@@1@49@@oe@16-12-2010 927647106@GENIA Treebank@formal@@1@S@We conclude that NF-kappa B activation could constitute one of the mechanisms whereby the expression of kappa B-responsive genes is enhanced in phagocytosing neutrophils.@@@@1@25@@oe@16-12-2010 927647107@GENIA Treebank@formal@@1@S@To our knowledge, this represents the first demonstration that phagocytic stimuli can induce NF-kappa B activation in human neutrophils.@@@@1@21@@oe@16-12-2010 927745001@GENIA Treebank@formal@@1@S@Surfactant protein A activates NF-kappa B in the THP-1 monocytic cell line.@@@@1@13@@oe@16-12-2010 927745002@GENIA Treebank@formal@@1@S@The expression of many genes for which products are involved in inflammation is controlled by the transcriptional regulator nuclear factor (NF)-kappa B.@@@@1@26@@oe@16-12-2010 927745003@GENIA Treebank@formal@@1@S@Because surfactant protein (SP) A is involved in local host defense in the lung and alters immune cell function by modulating the expression of proinflammatory cytokines as well as surface proteins involved in inflammation, we hypothesized that SP-A exerts its action, at least in part, via activation of NF-kappa B.@@@@1@56@@oe@16-12-2010 927745004@GENIA Treebank@formal@@1@S@We used gel shift assays to determine whether SP-A activated NF-kappa B in the THP-1 cell line, a human monocytic cell line.@@@@1@24@@oe@16-12-2010 927745005@GENIA Treebank@formal@@1@S@Activation of NF-kappa B in THP-1 cells by SP-A doses as low as 1 microgram/ml occurred within 30 min of SP-A treatment, peaked at 60 min, and then declined.@@@@1@32@@oe@16-12-2010 927745006@GENIA Treebank@formal@@1@S@This activation is inhibited by known inhibitors of NF-kappa B or by simultaneous treatment of the cells with surfactant lipids.@@@@1@21@@oe@16-12-2010 927745007@GENIA Treebank@formal@@1@S@Moreover, the NF-kappa B inhibitors blocked SP-A-dependent increases in tumor necrosis factor-alpha mRNA levels.@@@@1@16@@oe@16-12-2010 927745008@GENIA Treebank@formal@@1@S@These observations suggest a mechanism by which SP-A plays a role in the pathogenesis of some lung conditions and point to potential therapeutic measures that could be used to prevent SP-A induced inflammation in the lung.@@@@1@37@@oe@16-12-2010 927747801@GENIA Treebank@formal@@1@S@alpha-Tocopheryl succinate inhibits monocytic cell adhesion to endothelial cells by suppressing NF-kappa B mobilization.@@@@1@15@@oe@16-12-2010 927747802@GENIA Treebank@formal@@1@S@The adherence of monocytes to activated endothelium is an early event in atherogenesis.@@@@1@14@@oe@16-12-2010 927747803@GENIA Treebank@formal@@1@S@Because antioxidants have been considered to be of antiatherosclerotic potential, we investigated the effects of alpha-tocopherol (TCP) and its acetate and succinate esters on monocyte adhesion to cytokine-stimulated human umbilical vein endothelial cells (HUVEC).@@@@1@40@@oe@16-12-2010 927747804@GENIA Treebank@formal@@1@S@Endothelial cells were treated with TCP, alpha-tocopherol acetate (TCP acetate), or alpha-tocopheryl succinate (TCP succinate) before stimulation with tumor necrosis factor-alpha (TNF-alpha; 10 U/ml, 6 h) or interleukin-1 beta (IL-1 beta; 10 U/ml, 6 h).@@@@1@50@@oe@16-12-2010 927747805@GENIA Treebank@formal@@1@S@Cytokine-stimulated cell surface expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) and E-selectin (ELAM-1, CD62E), but not of intercellular adhesion molecule-1 (ICAM-1, CD54), was time- and dose-dependently inhibited by TCP succinate but not by TCP or TCP acetate.@@@@1@51@@oe@16-12-2010 927747806@GENIA Treebank@formal@@1@S@TCP succinate (200 microM, 24 h) reduced TNF-induced VCAM-1 and E-selectin expression from a specific mean fluorescence intensity of 151 +/- 28 to 12 +/- 4 channels and from 225 +/- 38 to 79 +/- 21 channels, respectively.@@@@1@43@@oe@16-12-2010 927747807@GENIA Treebank@formal@@1@S@Succinate alone had no effect.@@@@1@6@@oe@16-12-2010 927747808@GENIA Treebank@formal@@1@S@Decreased adhesion molecule expression was associated with a reduction of monocytic cell adhesion.@@@@1@14@@oe@16-12-2010 927747809@GENIA Treebank@formal@@1@S@TCP succinate (20 microM, 72 h), but not TCP (200 microM, 72 h), reduced U-937 cell adhesion to TNF-alpha-stimulated (10 U/ml, 6 h) HUVEC by 30% (P < 0.025) and to IL-1 beta-stimulated HUVEC by 56% (P < 0.010).@@@@1@57@@oe@16-12-2010 927747810@GENIA Treebank@formal@@1@S@Electrophoretic mobility-shift assays of HUVEC nuclear proteins revealed a decrease in TNF-alpha-stimulated nuclear factor-kappa B (NF-kappa B) activation after pretreatment of HUVEC with TCP succinate but not with TCP, TCP acetate, or succinate alone.@@@@1@39@@oe@16-12-2010 927747811@GENIA Treebank@formal@@1@S@In conclusion, we demonstrate that the vitamin E derivative TCP succinate prevents monocytic cell adhesion to cytokine-stimulated endothelial cells by inhibiting the activation of NF-kappa B, further emphasizing the antiatherosclerotic potential of lipid soluble antioxidants.@@@@1@38@@oe@16-12-2010 927749901@GENIA Treebank@formal@@1@S@Distinct mechanisms for N-acetylcysteine inhibition of cytokine-induced E-selectin and VCAM-1 expression.@@@@1@12@@oe@16-12-2010 927749902@GENIA Treebank@formal@@1@S@We have examined the effects of N-acetyl-L-cysteine (NAC), a well-characterized, thiol-containing antioxidant, on agonist-induced monocytic cell adhesion to endothelial cells (EC).@@@@1@29@@oe@16-12-2010 927749903@GENIA Treebank@formal@@1@S@NAC inhibited interleukin-1 (IL-1 beta)-induced, but not basal, adhesion with 50% inhibition at approximately 20 mM.@@@@1@23@@oe@16-12-2010 927749904@GENIA Treebank@formal@@1@S@Monocytic cell adhesion to EC in response to tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), alpha-thrombin, or phorbol 12-myristate 13-acetate (PMA) was similarly inhibited by NAC.@@@@1@35@@oe@16-12-2010 927749905@GENIA Treebank@formal@@1@S@Unlike published studies with pyrrolidinedithiocarbamate, which specifically inhibited vascular cell adhesion molecule 1 (VCAM-1), NAC inhibited IL-1 beta-induced mRNA and cell surface expression of both E-selectin and VCAM-1.@@@@1@33@@oe@16-12-2010 927749906@GENIA Treebank@formal@@1@S@NAC had no effect on the half-life of E-selectin or VCAM-1 mRNA.@@@@1@13@@oe@16-12-2010 927749907@GENIA Treebank@formal@@1@S@Although NAC reduced nuclear factor-kappa B (NF-kappa B) activation in EC as measured by gel-shift assays using an oligonucleotide probe corresponding to the consensus NF-kappa B binding sites of the VCAM-1 gene (VCAM-NF-kappa B), the antioxidant had no appreciable effect when an oligomer corresponding to the consensus NF-kappa B binding site of the E-selectin gene (E-selectin-NF-kappa B) was used.@@@@1@67@@oe@16-12-2010 927749908@GENIA Treebank@formal@@1@S@Because NF-kappa B has been reported to be redox sensitive, we studied the effects of NAC on the EC redox environment.@@@@1@23@@oe@16-12-2010 927749909@GENIA Treebank@formal@@1@S@NAC caused an expected dramatic increase in the reduced glutathione (GSH) levels in EC.@@@@1@17@@oe@16-12-2010 927749910@GENIA Treebank@formal@@1@S@In vitro studies demonstrated that whereas the binding affinity of NF-kappa B to the VCAM-NF-kappa B oligomer peaked at a GSH-to-oxidized glutathione (GSSG) ratio of approximately 200 and decreased at higher ratios, the binding to the E-selectin-NF-kappa B oligomer appeared relatively unaffected even at ratios > 400, i.e., those achieved in EC treated with 40 mM NAC.@@@@1@63@@oe@16-12-2010 927749911@GENIA Treebank@formal@@1@S@These results suggest that NF-kappa B binding to its consensus sequences in the VCAM-1 and E-selectin gene exhibits marked differences in redox sensitivity, allowing for differential gene expression regulated by the same transcription factor.@@@@1@36@@oe@16-12-2010 927749912@GENIA Treebank@formal@@1@S@Our data also demonstrate that NAC increases the GSH-to-GSSG ratio within the EC suggesting one possible mechanism through which this antioxidant inhibits agonist-induced monocyte adhesion to EC.@@@@1@28@@oe@16-12-2010 927833401@GENIA Treebank@formal@@1@S@Human monocyte binding to fibronectin enhances IFN-gamma-induced early signaling events.@@@@1@11@@oe@16-12-2010 927833402@GENIA Treebank@formal@@1@S@Leukocyte integrins are fundamentally important in modulating adhesion to extracellular matrix components and to other cells.@@@@1@17@@oe@16-12-2010 927833403@GENIA Treebank@formal@@1@S@This integrin-mediated adhesion controls leukocyte arrest and extravasation during the onset of inflammatory responses.@@@@1@15@@oe@16-12-2010 927833404@GENIA Treebank@formal@@1@S@Moreover, integrin-ligand interactions trigger signaling pathways that may influence leukocyte phenotype and function at sites of inflammation.@@@@1@19@@oe@16-12-2010 927833405@GENIA Treebank@formal@@1@S@In the current studies, we evaluated the combinatorial effects of monocyte adhesion and IFN-gamma on intracellular signaling pathways.@@@@1@20@@oe@16-12-2010 927833406@GENIA Treebank@formal@@1@S@IFN-gamma triggers a well-defined signal transduction pathway, which although not directly stimulated by monocyte adherence to fibronectin or arginine-glycine-aspartate (RGD)-coated substrata, was enhanced significantly in these matrix-adherent cells.@@@@1@34@@oe@16-12-2010 927833407@GENIA Treebank@formal@@1@S@Compared with monocytes in suspension or adherent on plastic surfaces, monocytes adherent to fibronectin or RGD exhibited a greater than threefold increase in steady state levels of IFN-gamma-induced mRNA for the high affinity Fc gammaRI receptor.@@@@1@38@@oe@16-12-2010 927833408@GENIA Treebank@formal@@1@S@By electrophoretic mobility shift assays, this increase in mRNA was associated with a 5- to 10-fold increase in the STAT1-containing DNA-binding complex that binds to Fc gammaRI promoter elements.@@@@1@31@@oe@16-12-2010 927833409@GENIA Treebank@formal@@1@S@Furthermore, the tyrosine phosphorylation of STAT1 and the tyrosine kinases JAK1 and JAK2 was enhanced significantly in RGD-adherent monocytes compared with control cells.@@@@1@25@@oe@16-12-2010 927833410@GENIA Treebank@formal@@1@S@These results suggest a novel mechanism by which integrin-mediated cell adhesion can modulate the magnitude of cytokine-induced signal transduction pathways, thereby amplifying cellular events leading to monocyte activation and inflammation.@@@@1@32@@oe@16-12-2010 927845501@GENIA Treebank@formal@@1@S@Regulation of inosine-5'-monophosphate dehydrogenase type II gene expression in human T cells.@@@@1@13@@oe@16-12-2010 927845502@GENIA Treebank@formal@@1@S@Role for a novel 5' palindromic octamer sequence.@@@@1@9@@oe@16-12-2010 927845503@GENIA Treebank@formal@@1@S@Expression of the gene encoding human inosine- 5'-monophosphate dehydrogenase (IMPDH) type II, an enzyme catalyzing the rate-limiting step in the generation of guanine nucleotides, is increased more than 10-fold in activated peripheral blood T lymphocytes and is required for T cell activation.@@@@1@46@@oe@16-12-2010 927845504@GENIA Treebank@formal@@1@S@We have examined the 5'-regulatory sequences that are important for the transcriptional regulation of this gene in T cells.@@@@1@20@@oe@16-12-2010 927845505@GENIA Treebank@formal@@1@S@DNase I mapping of genomic DNA identified a hypersensitive element near the transcription initiation site.@@@@1@16@@oe@16-12-2010 927845506@GENIA Treebank@formal@@1@S@Fine mapping by in vivo footprinting demonstrated five transcription factor binding sites that are occupied in both resting and activated peripheral blood T lymphocytes; these are tandem CRE motifs, a Sp1 site, an overlapping Egr-1/Sp1 site, and a novel palindromic octamer sequence (POS).@@@@1@50@@oe@16-12-2010 927845507@GENIA Treebank@formal@@1@S@The tandem CRE and POS sites are of major functional importance as judged by mutational and electrophoretic mobility shift analyses.@@@@1@21@@oe@16-12-2010 927845508@GENIA Treebank@formal@@1@S@These data provide evidence that expression of the human IMPDH type II gene is predominantly regulated by the nuclear factors ATF-2 and an as yet unidentified POS-binding protein.@@@@1@29@@oe@16-12-2010 927845509@GENIA Treebank@formal@@1@S@Additional major protein-DNA interactions do not occur within the promoter region after T lymphocyte activation, indicating a requirement for additional protein-protein interactions and/or post-translational modifications of pre-bound transcription factors to account for the observed increase in IMPDH type II gene expression.@@@@1@43@@oe@16-12-2010 928552701@GENIA Treebank@formal@@1@S@The carboxyl-terminal cytoplasmic domain of CD36 is required for oxidized low-density lipoprotein modulation of NF-kappaB activity by tumor necrosis factor-alpha.@@@@1@21@@oe@16-12-2010 928552702@GENIA Treebank@formal@@1@S@The binding of oxidized low-density lipoprotein (Ox LDL) by monocyte-macrophages causes pleiotropic effects, including changes in gene expression, and is thought to represent an early event in atherogenesis.@@@@1@33@@oe@16-12-2010 928552703@GENIA Treebank@formal@@1@S@The integral membrane glycoprotein CD36 appears to play a physiological role in binding and uptake of Ox LDL by monocyte-macrophages, although the molecular events associated with CD36-Ox LDL interaction are unknown.@@@@1@33@@oe@16-12-2010 928552704@GENIA Treebank@formal@@1@S@To approach this issue, we used CD36 transfected Chinese hampster ovary (CHO) cells, exposed them to Ox LDL, and determined changes in the activity of the transcription factor NF-kappaB.@@@@1@35@@oe@16-12-2010 928552705@GENIA Treebank@formal@@1@S@We report here that Ox LDL enhanced DNA binding activity of nuclear extracts to an NF-kappaB sequence following activation of CD36-producing CHO cells with the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha).@@@@1@34@@oe@16-12-2010 928552706@GENIA Treebank@formal@@1@S@This enhanced DNA binding activity was inhibited by coincubation of CD36 transfected cells with the human CD36-specific antibody OKM5.@@@@1@20@@oe@16-12-2010 928552707@GENIA Treebank@formal@@1@S@We also determined that activation of NF-kappaB DNA binding activity required an intact carboxyl-terminal cytoplasmic segment on CD36.@@@@1@19@@oe@16-12-2010 928552708@GENIA Treebank@formal@@1@S@Our results support the idea that human CD36 mediates signal transduction events in response to Ox LDL.@@@@1@18@@oe@16-12-2010 928577601@GENIA Treebank@formal@@1@S@Mutations in the TSC2 gene: analysis of the complete coding sequence using the protein truncation test (PTT).@@@@1@21@@oe@16-12-2010 928577602@GENIA Treebank@formal@@1@S@Mutations in the TSC2 gene on chromosome 16p13.3 are responsible for approximately 50% of familial tuberous sclerosis (TSC).@@@@1@22@@oe@16-12-2010 928577603@GENIA Treebank@formal@@1@S@The gene has 41 small exons spanning 45 kb of genomic DNA and encoding a 5.5 kb mRNA.@@@@1@19@@oe@16-12-2010 928577604@GENIA Treebank@formal@@1@S@Large germline deletions of TSC2 occur in <5% of cases, and a number of small intragenic mutations have been described.@@@@1@24@@oe@16-12-2010 928577605@GENIA Treebank@formal@@1@S@We analysed mRNA from 18 unrelated cases of TSC for TSC2 mutations using the protein truncation test (PTT).@@@@1@21@@oe@16-12-2010 928577606@GENIA Treebank@formal@@1@S@Three cases were predicted to be TSC2 mutations on the basis of linkage analysis or because a hamartoma from the patient showed loss of heterozygosity for 16p13.3 markers.@@@@1@29@@oe@16-12-2010 928577607@GENIA Treebank@formal@@1@S@Three overlapping PCR products, covering the complete coding sequence of mRNA, were generated from lymphoblastoid cell lines, translated into 35S-methionine labelled protein, and analysed by SDS-PAGE.@@@@1@31@@oe@16-12-2010 928577608@GENIA Treebank@formal@@1@S@PCR products showing PTT shifts were directly sequenced, and mutations confirmed by restriction enzyme digestion where possible.@@@@1@19@@oe@16-12-2010 928577609@GENIA Treebank@formal@@1@S@Six PTT shifts were identified.@@@@1@6@@oe@16-12-2010 928577610@GENIA Treebank@formal@@1@S@Five of these were caused by mutations predicted to produce a truncated protein: (i) a sporadic case showed a 32 bp deletion in exon 11, and a mutant mRNA without exon 11 was produced; the normal exon 10 was also spliced out; (ii) a sporadic case had a 1 bp deletion in exon 12 (1634delT); (iii) a TSC2-linked mother and daughter pair had a G-->T transversion in exon 23 (G2715T) introducing a cryptic splice site causing a 29 bp truncation of mRNA from exon 23; (iv) a sporadic case showed a 2 bp deletion in exon 36; (v) a sporadic case showed a 1 bp insertion disrupting the donor splice site of exon 37 (5007+2insA), resulting in the use of an upstream exonic cryptic splice site to cause a 29 bp truncation of mRNA from exon 37.@@@@1@164@@oe@16-12-2010 928577611@GENIA Treebank@formal@@1@S@In one case, the PTT shift was explained by in-frame splicing out of exon 10, in the presence of a normal exon 10 genomic sequence.@@@@1@28@@oe@16-12-2010 928577612@GENIA Treebank@formal@@1@S@Alternative splicing of exon 10 of the TSC2 gene may be a normal variant.@@@@1@15@@oe@16-12-2010 928577613@GENIA Treebank@formal@@1@S@Three 3rd base substitution polymorphisms were also detected during direct sequencing of PCR products.@@@@1@15@@oe@16-12-2010 928577614@GENIA Treebank@formal@@1@S@Confirmed mutations were identified in 28% of the families studied and on the assumption that half of the sporadic cases should have TSC2 mutations, a crude estimate of the detection rate would be 60%.@@@@1@38@@oe@16-12-2010 928577615@GENIA Treebank@formal@@1@S@This compares favourably with other screening methods used for TSC2, notably SSCP, and since PTT involves much less work it may be the method of choice.@@@@1@29@@oe@16-12-2010 929108901@GENIA Treebank@formal@@1@S@Transcriptional regulation during myelopoiesis.@@@@1@5@@oe@16-12-2010 929108902@GENIA Treebank@formal@@1@S@The coordinated production of all blood cells from a common stem cell is a highly regulated process involving successive stages of commitment and differentiation.@@@@1@25@@oe@16-12-2010 929108903@GENIA Treebank@formal@@1@S@From analyses of mice deficient in transcription factor genes and from the characterizations of chromosome breakpoints in human leukemias, it has become evident that transcription factors are important regulators of hematopoiesis.@@@@1@33@@oe@16-12-2010 929108904@GENIA Treebank@formal@@1@S@During myelopoiesis, which includes the development of granulocytic and monocytic lineages, transcription factors from several families are active, including AML1/CBF beta, C/EBP, Ets, c-Myb, HOX, and MZF-1.@@@@1@36@@oe@16-12-2010 929108905@GENIA Treebank@formal@@1@S@Few of these factors are expressed exclusively in myeloid cells; instead it appears that they cooperatively regulate transcription of myeloid-specific genes.@@@@1@23@@oe@16-12-2010 929108906@GENIA Treebank@formal@@1@S@Here we discuss recent advances in transcriptional regulation during myelopoiesis.@@@@1@11@@oe@16-12-2010 929535701@GENIA Treebank@formal@@1@S@Sp3 mediates transcriptional activation of the leukocyte integrin genes CD11C and CD11B and cooperates with c-Jun to activate CD11C.@@@@1@20@@oe@16-12-2010 929535702@GENIA Treebank@formal@@1@S@The leukocyte integrin genes CD11c and CD11b are expressed predominately in myelomonocytic cells.@@@@1@14@@oe@16-12-2010 929535703@GENIA Treebank@formal@@1@S@In previous experiments, the -70 to -65 and -121 to -103 regions of the CD11c promoter and the -66 to -59 region of the CD11b promoter were shown to be essential for Sp1- mediated activation of these genes.@@@@1@39@@oe@16-12-2010 929535704@GENIA Treebank@formal@@1@S@In vivo genomic footprinting had also revealed cell-specific binding of protein, presumably Sp1, to these regions.@@@@1@19@@oe@16-12-2010 929535705@GENIA Treebank@formal@@1@S@In this study, electrophoretic mobility shift analysis showed that the Sp1-related factor, Sp3, also binds at or near these same regions.@@@@1@25@@oe@16-12-2010 929535706@GENIA Treebank@formal@@1@S@Cotransfection of Sp3 along with CD11c promoter-luciferase constructs into Sp-deficient Drosophila Schneider 2 cells showed that Sp3 could activate the CD11c promoter.@@@@1@23@@oe@16-12-2010 929535707@GENIA Treebank@formal@@1@S@Deletion of both the -70 to -65 and -121 to -103 regions of the CD11c promoter resulted in the loss of activation by Sp3.@@@@1@25@@oe@16-12-2010 929535708@GENIA Treebank@formal@@1@S@Both sites showed activation by Sp3; however, the -70 to -65 region was more responsive to Sp3 than to Sp1.@@@@1@23@@oe@16-12-2010 929535709@GENIA Treebank@formal@@1@S@Similar transfection analysis of the -66 to -59 region of the CD11b promoter showed Sp3-dependent expression.@@@@1@17@@oe@16-12-2010 929535710@GENIA Treebank@formal@@1@S@Further, cotransfection analysis in Drosophila cells showed that Sp3, as was previously shown for Sp1, also synergizes with c-Jun to activate CD11c.@@@@1@26@@oe@16-12-2010 929535711@GENIA Treebank@formal@@1@S@Antisense experiments that knocked out endogenous Sp3 expression in the myelomocytic cell line, HL60, revealed that Sp3 participates in activation of the CD11c and CD11b promoters in vivo.@@@@1@31@@oe@16-12-2010 929939901@GENIA Treebank@formal@@1@S@Genomic organization, sequence, and transcriptional regulation of the human eotaxin gene.@@@@1@14@@oe@16-12-2010 929939902@GENIA Treebank@formal@@1@S@Eotaxin is an eosinophil specific beta-chemokine assumed to be involved in eosinophilic inflammatory diseases such as atopic dermatitis, allergic rhinitis, asthma and parasitic infections.@@@@1@27@@oe@16-12-2010 929939903@GENIA Treebank@formal@@1@S@Its expression is stimulus- and cell-specific.@@@@1@7@@oe@16-12-2010 929939904@GENIA Treebank@formal@@1@S@We here describe the genomic organisation (3 exons of 132, 112 and 542 bp and 2 introns of 1211 and 378 bp) and sequence including 3 kb of DNA from the immediate 5' upstream region of the human eotaxin gene.@@@@1@44@@oe@16-12-2010 929939905@GENIA Treebank@formal@@1@S@Among the regulatory promoter elements potentially regulating eotaxin gene expression and/or mediating the effects of anti-inflammatory drugs we identified consensus sequences known to interact with nuclear factors like NF-IL6, AP-1, a NF-kappa-B like consensus sequence and gamma-interferon- as well as glucocorticoid response elements.@@@@1@46@@oe@16-12-2010 929945501@GENIA Treebank@formal@@1@S@Vitamin D receptor: no evidence for allele-specific mRNA stability in cells which are heterozygous for the Taq I restriction enzyme polymorphism.@@@@1@23@@oe@16-12-2010 929945502@GENIA Treebank@formal@@1@S@Allelic variations of the vitamin D receptor (VDR) gene have been associated with the risk of developing prostate cancer in men and osteoporosis in postmenopausal women.@@@@1@29@@oe@16-12-2010 929945503@GENIA Treebank@formal@@1@S@Three RFLPs (TaqI, ApaI, BsmI) define two common haplotypes: BAt and baT.@@@@1@18@@oe@16-12-2010 929945504@GENIA Treebank@formal@@1@S@None of these polymorphisms change the translated protein.@@@@1@9@@oe@16-12-2010 929945505@GENIA Treebank@formal@@1@S@Since sequence variations in the 3' UTR of VDR have been linked to the different haplotypes, investigators have proposed that the stability of VDR mRNA is influenced by allelic variations.@@@@1@32@@oe@16-12-2010 929945506@GENIA Treebank@formal@@1@S@Indirect evidence suggested that allele T is less stable than allele t.@@@@1@13@@oe@16-12-2010 929945507@GENIA Treebank@formal@@1@S@In this study, we used a RT-PCR based approach to compare the stability of the big T and small t allele in normal heterozygous lymphocytes and the heterozygous cell lines NB4 (myeloid leukemia) and PC-3 and DU 145 (prostate cancers).@@@@1@46@@oe@16-12-2010 929945508@GENIA Treebank@formal@@1@S@In all three cases, we did not find a significant difference in stability.@@@@1@15@@oe@16-12-2010 929945509@GENIA Treebank@formal@@1@S@Interestingly, we consistently observed 30% less RT-PCR product derived from the small t allele mRNA in steady state, a finding which also speaks against a higher stability of the small t allele mRNA.@@@@1@37@@oe@16-12-2010 929945510@GENIA Treebank@formal@@1@S@These results indicate a variation in transcriptional regulation rather than mRNA stability between the alleles.@@@@1@16@@oe@16-12-2010 929945511@GENIA Treebank@formal@@1@S@We hypothesize that an unknown gene or genes in linkage with the polymorphisms is (are) responsible for the relationship between risk of prostate cancer and VDR polymorphisms.@@@@1@30@@oe@16-12-2010 929958901@GENIA Treebank@formal@@1@S@Rel/NF-kappa B transcription factors and the control of apoptosis.@@@@1@10@@oe@16-12-2010 929958902@GENIA Treebank@formal@@1@S@The process of apoptosis is used to eliminate unwanted cells from a wide variety of organisms.@@@@1@17@@oe@16-12-2010 929958903@GENIA Treebank@formal@@1@S@Various extracellular signals, often converging in common intracellular pathways, can induce apoptosis in a cell-type-specific fashion.@@@@1@19@@oe@16-12-2010 929958904@GENIA Treebank@formal@@1@S@Recent work from several laboratories has demonstrated that Rel/NF-kappa B transcription factors regulate apoptosis in many cell types.@@@@1@19@@oe@16-12-2010 929958905@GENIA Treebank@formal@@1@S@In most cells, Rel/NF-kappa B transcription factors appear to mediate survival signals that protect cells from apoptosis; however, under some circumstances, activation of these factors may also promote apoptosis.@@@@1@34@@oe@16-12-2010 929959001@GENIA Treebank@formal@@1@S@The role of Rel/NF-kappa B proteins in viral oncogenesis and the regulation of viral transcription.@@@@1@16@@oe@16-12-2010 929959002@GENIA Treebank@formal@@1@S@Rel/NF-kappa B is a ubiquitous transcription factor that consists of multiple polypeptide subunits, and is subject to complex regulatory mechanisms that involve protein-protein interactions, phosphorylation, ubiquitination, proteolytic degradation, and nucleocytoplasmic translocation.@@@@1@37@@oe@16-12-2010 929959003@GENIA Treebank@formal@@1@S@The sophisticated control of Rel/NF-kappa B activity is not surprising since this transcription factor is involved in a wide array of cellular responses to extracellular cues, associated with growth, development, apoptosis, and pathogen invasion.@@@@1@39@@oe@16-12-2010 929959004@GENIA Treebank@formal@@1@S@Thus, it is not unexpected that this versatile cellular homeostatic switch would be affected by a variety of viral pathogens, which have evolved mechanisms to utilize various aspects of Rel/NF-kappa B activity to facilitate their replication, cell survival and possibly evasion of immune responses.@@@@1@48@@oe@16-12-2010 929959005@GENIA Treebank@formal@@1@S@This review will cover the molecular mechanisms that are utilized by mammalian oncogenic viruses to affect the activity of Rel/NF-kappa B transcription factors and the role of Rel/NF-kappa B in the regulation of viral gene expression and replication.@@@@1@39@@oe@16-12-2010 930068701@GENIA Treebank@formal@@1@S@Transcription factor Egr-1 activity down-regulates Fas and CD23 expression in B cells.@@@@1@13@@oe@16-12-2010 930068702@GENIA Treebank@formal@@1@S@Activation of mature B cells via Ag receptor cross-linking induces transient expression of the transcription factor Egr-1.@@@@1@18@@oe@16-12-2010 930068703@GENIA Treebank@formal@@1@S@Although the activating signals leading to Egr-1 induction have been studied extensively, little is known about the genes that are placed further downstream within this activation cascade and that are transcriptionally regulated by Egr-1.@@@@1@36@@oe@16-12-2010 930068704@GENIA Treebank@formal@@1@S@To identify such target genes, we established Egr-1-overexpressing transfectants from the murine B cell line K46 and from human Ramos B cells.@@@@1@24@@oe@16-12-2010 930068705@GENIA Treebank@formal@@1@S@All clones derived from K46 B cells showed increased expression of CD44.@@@@1@13@@oe@16-12-2010 930068706@GENIA Treebank@formal@@1@S@Most interestingly, expression of CD95 (Fas/Apo-1) and of CD23 was down-regulated in all K46 transfectants.@@@@1@19@@oe@16-12-2010 930068707@GENIA Treebank@formal@@1@S@As a consequence, they became resistant to apoptosis induced by anti-CD95 Ab treatment.@@@@1@15@@oe@16-12-2010 930068708@GENIA Treebank@formal@@1@S@Similarly, the Egr-1-expressing Ramos cells showed reduced levels of CD95 expression.@@@@1@13@@oe@16-12-2010 930068709@GENIA Treebank@formal@@1@S@Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule.@@@@1@26@@oe@16-12-2010 930068710@GENIA Treebank@formal@@1@S@In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription.@@@@1@34@@oe@16-12-2010 930574901@GENIA Treebank@formal@@1@S@Selection of down-regulated sequences along the monocytic differentiation of leukemic HL60 cells.@@@@1@13@@oe@16-12-2010 930574902@GENIA Treebank@formal@@1@S@In order to dissect the molecular mechanisms of monocytic differentiation we have developed a subtractive hybridisation method based on a simplified 'representational difference analysis'.@@@@1@27@@oe@16-12-2010 930574903@GENIA Treebank@formal@@1@S@We have selected 16 sequences and confirmed their down-regulation along the TPA-induced monocytic differentiation of HL60 cells.@@@@1@18@@oe@16-12-2010 930574904@GENIA Treebank@formal@@1@S@Among these sequences we have identified the alpha-tubulin, the TaxREB protein and two ribosomal protein sequences which had not been previously described as differentially expressed.@@@@1@27@@oe@16-12-2010 930574905@GENIA Treebank@formal@@1@S@These results add to our knowledge about the molecules implicated along the monocytic differentiation and growth arrest of leukemic cells and provide a first step in the study of their respective roles.@@@@1@33@@oe@16-12-2010 930591901@GENIA Treebank@formal@@1@S@STAT3 is a serine kinase target in T lymphocytes.@@@@1@10@@oe@16-12-2010 930591902@GENIA Treebank@formal@@1@S@Interleukin 2 and T cell antigen receptor signals converge upon serine 727.@@@@1@13@@oe@16-12-2010 930591903@GENIA Treebank@formal@@1@S@Interleukin 2 (IL-2) induces tyrosine phosphorylation of STATs 3 and 5 (signal transducer and activator of transcription).@@@@1@22@@oe@16-12-2010 930591904@GENIA Treebank@formal@@1@S@We now show that IL-2 regulation of STAT3 proteins in T cells is a complex response involving activation of two forms of STAT3: 90-kDa STAT3alpha and an 83-kDa carboxyl-terminal truncated STAT3beta.@@@@1@33@@oe@16-12-2010 930591905@GENIA Treebank@formal@@1@S@The phosphorylation of STAT proteins on serine residues is also required for competent STAT transcription.@@@@1@16@@oe@16-12-2010 930591906@GENIA Treebank@formal@@1@S@A critical serine phosphorylation site in STAT3alpha is at position 727.@@@@1@12@@oe@16-12-2010 930591907@GENIA Treebank@formal@@1@S@In this study we have produced an antisera specific for STAT3alpha proteins phosphorylated on serine 727 and used this to monitor the phosphorylation of this residue during T lymphocyte activation.@@@@1@31@@oe@16-12-2010 930591908@GENIA Treebank@formal@@1@S@Our results show that phosphorylation of STAT3alpha on serine 727 is not constitutive in quiescent T cells but can be induced by the cytokine IL-2.@@@@1@26@@oe@16-12-2010 930591909@GENIA Treebank@formal@@1@S@Interestingly, triggering of the T cell antigen receptor complex or activation of protein kinase C with phorbol esters also induces phosphorylation of serine 727 but without simultaneously inducing STAT3 tyrosine phosphorylation or DNA binding.@@@@1@36@@oe@16-12-2010 930591910@GENIA Treebank@formal@@1@S@Hence, the present results show that STAT3 serine phosphorylation can be regulated independently of the tyrosine phosphorylation of this molecule.@@@@1@22@@oe@16-12-2010 930591911@GENIA Treebank@formal@@1@S@IL-2 and T cell antigen receptor complex induction of STAT3alpha serine 727 phosphorylation is dependent on the activity of the MEK/ERK pathway.@@@@1@23@@oe@16-12-2010 930591912@GENIA Treebank@formal@@1@S@Previous studies have identified H-7-sensitive kinase pathways that regulate STAT3 DNA binding.@@@@1@13@@oe@16-12-2010 930591913@GENIA Treebank@formal@@1@S@We show that H-7-sensitive pathways regulate STAT3 DNA binding in T cells.@@@@1@13@@oe@16-12-2010 930591914@GENIA Treebank@formal@@1@S@Nevertheless, we show that H-7-sensitive kinases do not regulate STAT3 tyrosine phosphorylation or phosphorylation of serine 727.@@@@1@19@@oe@16-12-2010 930591915@GENIA Treebank@formal@@1@S@These results thus show that STAT3 proteins are targets for multiple kinase pathways in T cells and can integrate signals from both cytokine receptors and antigen receptors.@@@@1@28@@oe@16-12-2010 930613401@GENIA Treebank@formal@@1@S@Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water.@@@@1@18@@oe@16-12-2010 930613402@GENIA Treebank@formal@@1@S@1. In this study we hypothesized that in individuals with certain genetic makeup, MTBE, benzene or their metabolites act as adducts and may induce programmed cell death.@@@@1@31@@oe@16-12-2010 930613403@GENIA Treebank@formal@@1@S@2. Our study involved a group of 60 male and female subjects who were exposed to MTBE and benzene-contaminated water concentrations up to 76 PPB for MTBE and 14 PPB for benzene, for a period of 5 to 8 years.@@@@1@43@@oe@16-12-2010 930613404@GENIA Treebank@formal@@1@S@For comparison, we recruited a control group consisting of 32 healthy males and females with similar age distribution and without a history of exposure to MTBE or benzene.@@@@1@30@@oe@16-12-2010 930613405@GENIA Treebank@formal@@1@S@3. Peripheral blood lymphocytes (PBL) of both groups were tested for the percentage of apoptotic cells and cell cycle progression using flow cytometry.@@@@1@27@@oe@16-12-2010 930613406@GENIA Treebank@formal@@1@S@4. When apoptotic lymphocytes from exposed individuals were compared to apoptotic lymphocytes from the control group, statistically-significant differences between each mean group were detected (26.4 +/- 1.8 and 12.1 +/- 1.3, respectively), indicating an increased rate of apoptosis in 80.5% of exposed individuals (P < 0.0001, Mann-Whitney U-Test).@@@@1@59@@oe@16-12-2010 930613407@GENIA Treebank@formal@@1@S@MTBE and benzene-induced apoptosis is attributed to a discrete block within the cell cycle progression.@@@@1@16@@oe@16-12-2010 930613408@GENIA Treebank@formal@@1@S@Because cell cycle analysis showed that in PBL from chemically-exposed individuals, between 20-50% of cells were accumulated at the S-G2/M boundaries.@@@@1@24@@oe@16-12-2010 930613409@GENIA Treebank@formal@@1@S@5. One of the signaling molecules which mediates programmed cell death is nuclear factor Kappa-B (NF-kappa B).@@@@1@21@@oe@16-12-2010 930613410@GENIA Treebank@formal@@1@S@NF-kappa B was examined as one of the many molecular mechanisms for mediating cell death by MTBE and benzene.@@@@1@20@@oe@16-12-2010 930613411@GENIA Treebank@formal@@1@S@Indeed, addition of inhibitors of NF-kappa B activation pyrrolidine dithiocarbamate (PDTC), to the lymphocytes of the chemically-exposed group was capable of inhibiting programmed cell death by 40%.@@@@1@33@@oe@16-12-2010 930613412@GENIA Treebank@formal@@1@S@This reversal of apoptosis almost to the control level by inhibitor of NF-kappa B activation may indicate involvement of this signaling molecule in MTBE and benzene induction of programmed cell death.@@@@1@32@@oe@16-12-2010 930727101@GENIA Treebank@formal@@1@S@Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia.@@@@1@22@@oe@16-12-2010 930727102@GENIA Treebank@formal@@1@S@We have identified a novel gene, GR6, located within the leukemia breakpoint region of 3q21, that is normally expressed in early fetal development but not in adult peripheral blood.@@@@1@33@@oe@16-12-2010 930727103@GENIA Treebank@formal@@1@S@GR6 is activated in the UCSD-AML1 cell line and in a leukemic sample, both of which carry a t(3;3)(q21;q26).@@@@1@21@@oe@16-12-2010 930727104@GENIA Treebank@formal@@1@S@In UCSD-AML1, we have also identified fusion transcripts between the ecotropic viral insertion site I (EVI1) gene in 3q26 and GR6 and between EVI1 and Ribophorin I that maps 30 kb telomeric to GR6 in 3q21.@@@@1@40@@oe@16-12-2010 930727105@GENIA Treebank@formal@@1@S@All fusions splice the 5' ends of the 3q21 genes into exon 2 of the EVI1 gene, an event that is similar to the normal intergenic splicing of MDS1-EVI1 and to those previously documented in leukemias with t(3;21) and t(3;12), in which acute myelogenous leukemia 1-EVI1 fusions and ETV6-EVI1 fusions, respectively, occur.@@@@1@57@@oe@16-12-2010 930727106@GENIA Treebank@formal@@1@S@The Ribophorin I-EVI1 fusion in particular may be a common occurrence in t(3;3).@@@@1@14@@oe@16-12-2010 930930601@GENIA Treebank@formal@@1@S@Alcohol-induced regulation of nuclear regulatory factor-kappa beta in human monocytes.@@@@1@11@@oe@16-12-2010 930930602@GENIA Treebank@formal@@1@S@Acute ethanol exposure has the capacity to modulate immune functions, particularly, to down regulate monocyte production of inflammatory cytokines.@@@@1@22@@oe@16-12-2010 930930603@GENIA Treebank@formal@@1@S@However, the intracellular mechanisms for these effects of ethanol are yet to be understood.@@@@1@16@@oe@16-12-2010 930930604@GENIA Treebank@formal@@1@S@Considering that nuclear regulatory factor-kappa beta (NF-kappa B)/Rel is a common regulatory element of the promoter region of the inflammatory cytokine genes, herein, we tested the hypothesis that acute ethanol affects NF-kappa B activation in human monocytes.@@@@1@43@@oe@16-12-2010 930930605@GENIA Treebank@formal@@1@S@Adherence-isolated monocytes showed constitutive DNA binding activity of NF-kappa B.@@@@1@11@@oe@16-12-2010 930930606@GENIA Treebank@formal@@1@S@A clinically relevant dose (25 mM) of acute ethanol treatment in vitro increased NF-kappa B binding activity in monocytes with a preferential induction of the inhibitory, p50/p50, NF-kappa B/Rel homodimer, and resulted in no induction of the p65/p50 heterodimer.@@@@1@45@@oe@16-12-2010 930930607@GENIA Treebank@formal@@1@S@In contrast, lipopolysaccharide stimulation primarily induced the p65/p50 heterodimer that has been shown to result in gene activation.@@@@1@20@@oe@16-12-2010 930930608@GENIA Treebank@formal@@1@S@Thus, such unique activation of the inhibitory p50/p50 homodimer by acute ethanol treatment may result in inhibition rather than activation of NF-kappa B-regulated inflammatory cytokine genes.@@@@1@28@@oe@16-12-2010 930930609@GENIA Treebank@formal@@1@S@Consequently, these results suggest that physiologically relevant concentrations of ethanol may affect production of inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 by disrupting NF-kappa B signaling in monocytes.@@@@1@37@@oe@16-12-2010 931083601@GENIA Treebank@formal@@1@S@Four P-like elements are required for optimal transcription of the mouse IL-4 gene: involvement of a distinct set of nuclear factor of activated T cells and activator protein-1 family proteins.@@@@1@32@@oe@16-12-2010 931083602@GENIA Treebank@formal@@1@S@We previously identified the P sequence as a critical regulatory element of the human IL-4 promoter.@@@@1@17@@oe@16-12-2010 931083603@GENIA Treebank@formal@@1@S@In the mouse IL-4 promoter, there are five elements homologous to the human P sequence designated conserved lymphokine element 0 (CLE0), P, P2, P3 and P4.@@@@1@33@@oe@16-12-2010 931083604@GENIA Treebank@formal@@1@S@To characterize the role of these P-like elements and their binding factors in the native promoter, we did transient transfection and electrophoretic mobility shift assays (EMSA).@@@@1@30@@oe@16-12-2010 931083605@GENIA Treebank@formal@@1@S@Transfection of EL-4 cells with the IL-4 promoter-reporter constructs carrying mutated P-like elements showed that four P-like elements, CLE0, P, P2 and P4, but not P3, were required for optimal activation of the IL-4 promoter.@@@@1@41@@oe@16-12-2010 931083606@GENIA Treebank@formal@@1@S@EMSA showed that both constitutive and inducible complexes bound to CLE0, P, P2 and P4, whereas only a constitutive complex bound to P3.@@@@1@27@@oe@16-12-2010 931083607@GENIA Treebank@formal@@1@S@In competition and antibody supershift assays in EMSA, complexes formed with P or P2 proved to contain nuclear factor of activated T cells (NFAT) family proteins as major components.@@@@1@33@@oe@16-12-2010 931083608@GENIA Treebank@formal@@1@S@Activator protein (AP)-1 family proteins interacted with CLE0, P, P2 and P4.@@@@1@18@@oe@16-12-2010 931083609@GENIA Treebank@formal@@1@S@NFAT/AP-1 complex formed only with P and P2.@@@@1@9@@oe@16-12-2010 931083610@GENIA Treebank@formal@@1@S@Cross-competition assays among the P-like elements revealed element-specific and common complexes.@@@@1@12@@oe@16-12-2010 931083611@GENIA Treebank@formal@@1@S@Six tandem repeats of the P element linked to the SV40 promoter responded to phorbol 12-myristate 13-acetate, while that of other elements did not.@@@@1@26@@oe@16-12-2010 931083612@GENIA Treebank@formal@@1@S@It would thus appear that components of each P-like element-binding complexes are not identical and may coordinately contribute to transcriptional activity.@@@@1@22@@oe@16-12-2010 931101001@GENIA Treebank@formal@@1@S@Expression of bcl-6 protein in normal skin and epidermal neoplasms.@@@@1@11@@oe@16-12-2010 931101002@GENIA Treebank@formal@@1@S@Bcl-6 protein is a recently identified novel transcription factor whose deregulated expression is associated with diffuse large B cell lymphomas.@@@@1@21@@oe@16-12-2010 931101003@GENIA Treebank@formal@@1@S@It was recently shown by us that the protein is located in germinal center B cells and their neoplastic counterparts.@@@@1@21@@oe@16-12-2010 931101004@GENIA Treebank@formal@@1@S@In the present study, the expression of bcl-6 protein on normal epidermis, benign, and malignant tumors originating from epidermal cells, and squamous cell carcinoma (SCC) cell lines are investigated.@@@@1@36@@oe@16-12-2010 931101005@GENIA Treebank@formal@@1@S@With the use of immunohistochemistry, bcl-6 protein was shown to stain intensely on normal prickle cells, but none to only slightly on epidermal basal cells.@@@@1@28@@oe@16-12-2010 931101006@GENIA Treebank@formal@@1@S@Papillomas and keratoacanthomas copied their normal counterparts in the mode of expression.@@@@1@13@@oe@16-12-2010 931101007@GENIA Treebank@formal@@1@S@Various levels of expression were found on seborrheic keratoses, while the expression level on basal cell epitheliomas was low.@@@@1@21@@oe@16-12-2010 931101008@GENIA Treebank@formal@@1@S@Peculiarly, eccrine poromas and undifferentiated spindle-shaped basal cell epitheliomas were totally unstained.@@@@1@14@@oe@16-12-2010 931101009@GENIA Treebank@formal@@1@S@Squamous cell carcinomas showed a variety of expression levels, while two undifferentiated spindle-shaped carcinomas and one undifferentiated SCC cell line remained unstained.@@@@1@24@@oe@16-12-2010 931101010@GENIA Treebank@formal@@1@S@These results suggest that the expression of bcl-6 protein may be associated with morphological differentiation in normal and neoplastic epidermal cells.@@@@1@22@@oe@16-12-2010 931183001@GENIA Treebank@formal@@1@S@The ability of BHRF1 to inhibit apoptosis is dependent on stimulus and cell type.@@@@1@15@@oe@16-12-2010 931183002@GENIA Treebank@formal@@1@S@The development of resistance to host defense mechanisms such as tumor necrosis factor (TNF)- and Fas-mediated apoptosis of transformed or virus-infected cells may be a critical component in the development of disease.@@@@1@36@@oe@16-12-2010 931183003@GENIA Treebank@formal@@1@S@To find genes that protect cells from apoptosis, we used an expression cloning strategy and identified BHRF1, an Epstein-Barr virus (EBV) early-lytic-cycle protein with distant homology to Bcl-2, as an anti-apoptosis protein.@@@@1@38@@oe@16-12-2010 931183004@GENIA Treebank@formal@@1@S@Expression of BHRF1 in MCF-Fas cells conferred nearly complete resistance against both anti-Fas antibody and TNF-mediated apoptosis.@@@@1@18@@oe@16-12-2010 931183005@GENIA Treebank@formal@@1@S@In addition, BHRF1 protected these cells from monocyte-mediated killing but failed to protect them from killing mediated by lymphokine-activated killer cells.@@@@1@23@@oe@16-12-2010 931183006@GENIA Treebank@formal@@1@S@The ability of BHRF1 to protect MCF-Fas cells from apoptosis induced by various stimuli was identical to that of Bcl-2 and Bcl-xL.@@@@1@23@@oe@16-12-2010 931183007@GENIA Treebank@formal@@1@S@Moreover, the mechanism of action of BHRF1 resembled that of Bcl-2 and Bcl-xL as it inhibited TNF- and anti-Fas-induced activation of two enzymes participating in the apoptosis pathway, cytosolic phospholipase A2 and caspase-3/CPP32, but did not interfere with the activation of NF-kappaB-like transcription factors.@@@@1@48@@oe@16-12-2010 931183008@GENIA Treebank@formal@@1@S@A putative function of BHRF1 in EBV-infected epithelial cells may be to protect virus-infected cells from TNF- and/or anti-Fas- induced cell death in order to maximize virus production.@@@@1@28@@oe@16-12-2010 931183009@GENIA Treebank@formal@@1@S@Surprisingly, expression of neither BHRF1 nor Bcl-2 in a B-cell line, BJAB, protected the cells from anti-Fas-mediated apoptosis even though they increased the survival of serum-starved cells.@@@@1@31@@oe@16-12-2010 931183010@GENIA Treebank@formal@@1@S@Thus, the protective role of BHRF1 against apoptosis resembles that of Bcl-2 in being cell type specific and dependent on the apoptotic stimulus.@@@@1@25@@oe@16-12-2010 931191201@GENIA Treebank@formal@@1@S@Negative regulation by HLA-DO of MHC class II-restricted antigen processing.@@@@1@11@@oe@16-12-2010 931191202@GENIA Treebank@formal@@1@S@HLA-DM is a major histocompatibility complex (MHC) class II-like molecule that facilitates antigen processing by catalyzing the exchange of invariant chain-derived peptides (CLIP) from class II molecules for antigenic peptides.@@@@1@35@@oe@16-12-2010 931191203@GENIA Treebank@formal@@1@S@HLA-DO is a second class II-like molecule that physically associates with HLA-DM in B cells.@@@@1@16@@oe@16-12-2010 931191204@GENIA Treebank@formal@@1@S@HLA-DO was shown to block HLA-DM function.@@@@1@8@@oe@16-12-2010 931191205@GENIA Treebank@formal@@1@S@Purified HLA-DM-DO complexes could not promote peptide exchange in vitro.@@@@1@11@@oe@16-12-2010 931191206@GENIA Treebank@formal@@1@S@Expression of HLA-DO in a class II+ and DM+, DO- human T cell line caused the accumulation of class II-CLIP complexes, indicating that HLA-DO blocked DM function in vivo and suggesting that HLA-DO is an important modulator of class II-restricted antigen processing.@@@@1@45@@oe@16-12-2010 931192101@GENIA Treebank@formal@@1@S@NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily.@@@@1@15@@oe@16-12-2010 931192102@GENIA Treebank@formal@@1@S@Activation of the nuclear factor of activated T cells transcription factor (NF-AT) is a key event underlying lymphocyte action.@@@@1@22@@oe@16-12-2010 931192103@GENIA Treebank@formal@@1@S@The CAML (calcium-modulator and cyclophilin ligand) protein is a coinducer of NF-AT activation when overexpressed in Jurkat T cells.@@@@1@22@@oe@16-12-2010 931192104@GENIA Treebank@formal@@1@S@A member of the tumor necrosis factor receptor superfamily was isolated by virtue of its affinity for CAML.@@@@1@19@@oe@16-12-2010 931192105@GENIA Treebank@formal@@1@S@Cross-linking of this lymphocyte-specific protein, designated TACI (transmembrane activator and CAML-interactor), on the surface of transfected Jurkat cells with TACI-specific antibodies led to activation of the transcription factors NF-AT, AP-1, and NFkappaB.@@@@1@39@@oe@16-12-2010 931192106@GENIA Treebank@formal@@1@S@TACI-induced activation of NF-AT was specifically blocked by a dominant-negative CAML mutant, thus implicating CAML as a signaling intermediate.@@@@1@21@@oe@16-12-2010 931202301@GENIA Treebank@formal@@1@S@Cooperation of Spi-1/PU.1 with an activated erythropoietin receptor inhibits apoptosis and Epo-dependent differentiation in primary erythroblasts and induces their Kit ligand-dependent proliferation.@@@@1@23@@oe@16-12-2010 931202302@GENIA Treebank@formal@@1@S@Spi-1/PU.1 is a myeloid- and B-cell specific transcription factor which is also involved in Friend virus-induced murine erythroleukemia.@@@@1@19@@oe@16-12-2010 931202303@GENIA Treebank@formal@@1@S@The pre-leukemic phase of Friend erythroleukemia results from activation of the erythropoietin receptor (EpoR) by the spleen focus forming virus (SFFV) envelope glycoprotein, followed by the emergence of leukemic clones characterized by overexpression of Spi-1 and mutation of the p53 tumor suppressor gene.@@@@1@49@@oe@16-12-2010 931202304@GENIA Treebank@formal@@1@S@We developed a heterologous system to analyze the contribution of these alterations to the induction of primary erythroblast transformation.@@@@1@20@@oe@16-12-2010 931202305@GENIA Treebank@formal@@1@S@Avian erythroblasts expressing the activated mouse EpoR(R129C) differentiated into erythrocytes in response to hEpo.@@@@1@18@@oe@16-12-2010 931202306@GENIA Treebank@formal@@1@S@Expression of Spi-1 in these cells inhibited this ability to differentiate and rescued the cells from the apoptotic cell death program normally induced upon hEpo withdrawal.@@@@1@27@@oe@16-12-2010 931202307@GENIA Treebank@formal@@1@S@Although devoid of any effect by itself, a mutant p53 cooperated with Spi-1 and EpoR(R129C) to reinforce both phenotypes.@@@@1@24@@oe@16-12-2010 931202308@GENIA Treebank@formal@@1@S@Analysis of erythroblasts co-expressing Spi-1 and the wild-type mouse EpoR showed that differentiation arrest and inhibition of apoptosis depended on specific cooperation between Spi-1 and EpoR(R129C).@@@@1@30@@oe@16-12-2010 931202309@GENIA Treebank@formal@@1@S@This cooperation was also required to induce the sustained proliferation of differentiation-blocked erythroblasts in response to ligand activation of the endogenous tyrosine kinase receptor c-Kit.@@@@1@26@@oe@16-12-2010 931202310@GENIA Treebank@formal@@1@S@These results show that Spi-1/PU.1 requires signals emanating from specific cytokine and growth factor receptors to affect the survival, proliferation and differentiation control of primary erythroblasts.@@@@1@28@@oe@16-12-2010 931202311@GENIA Treebank@formal@@1@S@They also suggest that the function of Spi-1/PU.1 in the late phase of Friend leukemia requires specific signaling from the gp55-modified EpoR generated during the early phase of the disease.@@@@1@31@@oe@16-12-2010 931209401@GENIA Treebank@formal@@1@S@The DNA binding domain of the A-MYB transcription factor is responsible for its B cell-specific activity and binds to a B cell 110-kDa nuclear protein.@@@@1@26@@oe@16-12-2010 931209402@GENIA Treebank@formal@@1@S@Expression studies as well as the use of transgenic animals have demonstrated that the A-MYB transcription factor plays central and specific role in the regulation of mature B cell proliferation and/or differentiation.@@@@1@33@@oe@16-12-2010 931209403@GENIA Treebank@formal@@1@S@Furthermore, it is highly expressed in Burkitt's lymphoma cells and may participate in the pathogenesis of this disease.@@@@1@21@@oe@16-12-2010 931209404@GENIA Treebank@formal@@1@S@We have therefore investigated the transcriptional activity of A-MYB and its regulation in several human lymphoid cell lines using co-transfection assays and show that A-MYB is transcriptionally active in all the B cell lines studied, but not in T cells.@@@@1@42@@oe@16-12-2010 931209405@GENIA Treebank@formal@@1@S@In particular the best responder cell line was the Burkitt's cell line Namalwa.@@@@1@15@@oe@16-12-2010 931209406@GENIA Treebank@formal@@1@S@The activity of A-MYB in B and not T cells was observed when either an artificial construct or the c-MYC promoter was used as a reporter.@@@@1@27@@oe@16-12-2010 931209407@GENIA Treebank@formal@@1@S@Furthermore, the functional domains responsible for DNA binding, transactivation, and negative regulation, previously characterized in a fibroblast context, were found to have similar activity in B cells.@@@@1@33@@oe@16-12-2010 931209408@GENIA Treebank@formal@@1@S@The region of A-MYB responsible for the B cell specific activity was defined to be the N-terminal 218 amino acids containing the DNA binding domain.@@@@1@26@@oe@16-12-2010 931209409@GENIA Treebank@formal@@1@S@Finally, a 110-kDa protein has been identified in the nuclei of all the B, but not T, cell lines that specifically binds to this A-MYB N-terminal domain.@@@@1@31@@oe@16-12-2010 931209410@GENIA Treebank@formal@@1@S@We hypothesize that this 110-kDa protein may be a functionally important B cell-specific co-activator of A-MYB.@@@@1@17@@oe@16-12-2010 931219201@GENIA Treebank@formal@@1@S@Evidence that calcineurin is rate-limiting for primary human lymphocyte activation.@@@@1@11@@oe@16-12-2010 931219202@GENIA Treebank@formal@@1@S@Cyclosporine (CsA) is both a clinical immunosuppressive drug and a probe to dissect intracellular signaling pathways.@@@@1@19@@oe@16-12-2010 931219203@GENIA Treebank@formal@@1@S@In vitro, CsA inhibits lymphocyte gene activation by inhibiting the phosphatase activity of calcineurin (CN).@@@@1@19@@oe@16-12-2010 931219204@GENIA Treebank@formal@@1@S@In clinical use, CsA treatment inhibits 50-75% of CN activity in circulating leukocytes.@@@@1@16@@oe@16-12-2010 931219205@GENIA Treebank@formal@@1@S@We modeled this degree of CN inhibition in primary human leukocytes in vitro in order to study the effect of partial CN inhibition on the downstream signaling events that lead to gene activation.@@@@1@34@@oe@16-12-2010 931219206@GENIA Treebank@formal@@1@S@In CsA-treated leukocytes stimulated by calcium ionophore, the degree of reduction in CN activity was accompanied by a similar degree of inhibition of each event tested: dephosphorylation of nuclear factor of activated T cell proteins, nuclear DNA binding, activation of a transfected reporter gene construct, IFN-gamma and IL-2 mRNA accumulation, and IFN-gamma production.@@@@1@60@@oe@16-12-2010 931219207@GENIA Treebank@formal@@1@S@Furthermore, the degree of CN inhibition was reflected by a similar degree of reduction in lymphocyte proliferation and IFN-gamma production in the allogeneic mixed lymphocyte cultures.@@@@1@28@@oe@16-12-2010 931219208@GENIA Treebank@formal@@1@S@These data support the conclusion that CN activity is rate-limiting for the activation of primary human T lymphocytes.@@@@1@19@@oe@16-12-2010 931219209@GENIA Treebank@formal@@1@S@Thus, the reduction of CN activity observed in CsA-treated patients is accompanied by a similar degree of reduction in lymphocyte gene activation, and accounts for the immunosuppression observed.@@@@1@31@@oe@16-12-2010 931566301@GENIA Treebank@formal@@1@S@Tissue transglutaminase-dependent posttranslational modification of the retinoblastoma gene product in promonocytic cells undergoing apoptosis.@@@@1@15@@oe@16-12-2010 931566302@GENIA Treebank@formal@@1@S@The retinoblastoma gene product (pRB) plays an important role in controlling both cell release from the G1 phase and apoptosis.@@@@1@23@@oe@16-12-2010 931566303@GENIA Treebank@formal@@1@S@We show here that in the early phases of apoptosis, pRB is posttranslationally modified by a tissue transglutaminase (tTG)-catalyzed reaction.@@@@1@25@@oe@16-12-2010 931566304@GENIA Treebank@formal@@1@S@In fact, by employing a novel haptenized lysis synthetic substrate which allows the isolation of glutaminyl-tTG substrates in vivo, we identified pRB as a potential tTG substrate in U937 cells undergoing apoptosis.@@@@1@35@@oe@16-12-2010 931566305@GENIA Treebank@formal@@1@S@In keeping with this finding, we showed that apoptosis of U937 cells is characterized by the rapid disappearance of the 105,000- to 110,000-molecular-weight pRB forms concomitantly with the appearance of a smear of immunoreactive products with a molecular weight of greater than 250,000.@@@@1@45@@oe@16-12-2010 931566306@GENIA Treebank@formal@@1@S@The shift in pRB molecular weight was reproduced by adding exogenous purified tTG to extracts obtained from viable U937 cells and was prevented by dansylcadaverine, a potent enzyme inhibitor.@@@@1@31@@oe@16-12-2010 931566307@GENIA Treebank@formal@@1@S@The effect of the pRB posttranslational modification during apoptosis was investigated by determining the E2F-1 levels and by isolating and characterizing pRB-null clones from U937 cells.@@@@1@27@@oe@16-12-2010 931566308@GENIA Treebank@formal@@1@S@Notably, the lack of pRB in these U937-derived clones renders these p53-null cells highly resistant to apoptosis induced by serum withdrawal, calphostin C, and ceramide.@@@@1@29@@oe@16-12-2010 931566309@GENIA Treebank@formal@@1@S@Taken together, these data suggest that tTG, acting on the pRB protein, might play an important role in the cell progression through the death program.@@@@1@29@@oe@16-12-2010 931713101@GENIA Treebank@formal@@1@S@Cooperation of binding sites for STAT6 and NF kappa B/rel in the IL-4-induced up-regulation of the human IgE germline promoter.@@@@1@21@@oe@16-12-2010 931713102@GENIA Treebank@formal@@1@S@Ig heavy chain class switching is directed by cytokines inducing transcription from unrearranged CH genes.@@@@1@16@@oe@16-12-2010 931713103@GENIA Treebank@formal@@1@S@Subsequently, such primed cells can undergo switch recombination to express the selected new isotype.@@@@1@16@@oe@16-12-2010 931713104@GENIA Treebank@formal@@1@S@In the case of IgE class switching, IL-4 activates the IgE germline promoter by inducing the interaction of the transcription factor STAT6 (IL-4STAT) with a responsive DNA element in the proximal region of the promoter.@@@@1@39@@oe@16-12-2010 931713105@GENIA Treebank@formal@@1@S@This study describes the characterization of two additional cis-acting elements that interact with members of the NF kappa B/rel transcription factor family in an IL-4-independent fashion.@@@@1@27@@oe@16-12-2010 931713106@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assays show that the nucleoprotein complex formed on the upstream site (NF kappa B1) contains the classical p50/p65 heterodimer.@@@@1@25@@oe@16-12-2010 931713107@GENIA Treebank@formal@@1@S@The complex on the proximal site (NF kappa B2) appears to be composed of p50 and relB.@@@@1@20@@oe@16-12-2010 931713108@GENIA Treebank@formal@@1@S@IgE germline promoter reporter gene constructs carrying point mutations in the NF kappa B2 site were largely unresponsive to IL-4 stimulation in transient transfection experiments, while plasmids with similar mutations in the NF kappa B1 site responded to cytokine stimulation better than the wild-type promoter.@@@@1@47@@oe@16-12-2010 931713109@GENIA Treebank@formal@@1@S@The NF kappa B2 effect was dependent on the presence of the STAT6 binding site, demonstrating that the NF kappa B2 motif is necessary but not sufficient for mediating cytokine up-regulation.@@@@1@33@@oe@16-12-2010 931713110@GENIA Treebank@formal@@1@S@In addition, the combination of a NF kappa B/rel binding site and the STAT6 response element conferred IL-4 inducibility to a heterologous minimal promoter, while the individual sites had no effect.@@@@1@34@@oe@16-12-2010 931713111@GENIA Treebank@formal@@1@S@The available data suggest that the NF kappa B2 nucleoprotein complex may cooperate with DNA-bound STAT6 to achieve IL-4-dependent activation of the human IgE germline gene.@@@@1@27@@oe@16-12-2010 931715101@GENIA Treebank@formal@@1@S@Dual effects of LPS antibodies on cellular uptake of LPS and LPS-induced proinflammatory functions.@@@@1@15@@oe@16-12-2010 931715102@GENIA Treebank@formal@@1@S@Human phagocytes recognize bacterial LPS (endotoxin) through membrane CD14 (mCD14), a proinflammatory LPS receptor.@@@@1@20@@oe@16-12-2010 931715103@GENIA Treebank@formal@@1@S@This study tested the hypothesis that anti-LPS Abs neutralize endotoxin by blocking cellular uptake through mCD14.@@@@1@17@@oe@16-12-2010 931715104@GENIA Treebank@formal@@1@S@Ab-associated changes in the uptake and cellular distribution of FITC-LPS were assessed by flow cytometry and laser scanning confocal microscopy in human CD14-transfected Chinese hamster ovary fibroblasts (CHO-CD14 cells) and human peripheral blood monocytes.@@@@1@37@@oe@16-12-2010 931715105@GENIA Treebank@formal@@1@S@LPS core- and O-side chain-specific mAbs inhibited mCD14-mediated LPS uptake by both cell types in the presence of serum.@@@@1@20@@oe@16-12-2010 931715106@GENIA Treebank@formal@@1@S@O-side chain-specific mAb concurrently enhanced complement-dependent LPS uptake by monocytes through complement receptor-1 (CR1) and uptake by CHO-CD14 cells involving another heat-labile serum factor(s) and cell-associated recognition molecule(s).@@@@1@37@@oe@16-12-2010 931715107@GENIA Treebank@formal@@1@S@Core-specific mAb inhibited mCD14-mediated uptake of homologous and heterologous LPS, while producing less concurrent enhancement of non-mCD14-mediated LPS uptake.@@@@1@21@@oe@16-12-2010 931715108@GENIA Treebank@formal@@1@S@The modulation by anti-LPS mAbs of mCD14-mediated LPS uptake was associated with inhibition of LPS-induced nuclear factor-kappaB (NF-kappaB) translocation and TNF-alpha secretion in CHO-CD14 cells and monocytes, respectively, while mAb enhancement of non-mCD14-mediated LPS uptake stimulated these activities.@@@@1@43@@oe@16-12-2010 931715109@GENIA Treebank@formal@@1@S@LPS-specific Abs thus mediate anti-inflammatory and proinflammatory functions, respectively, by preventing target cell uptake of LPS through mCD14 and augmenting uptake through CR1 or other cell receptors.@@@@1@30@@oe@16-12-2010 932288901@GENIA Treebank@formal@@1@S@The A-myb transcription factor in neoplastic and normal B cells.@@@@1@11@@oe@16-12-2010 932288902@GENIA Treebank@formal@@1@S@The myb family of transcription factors has been strongly implicated in the regulation of cell growth and differentiation in the haematopoietic system.@@@@1@23@@oe@16-12-2010 932288903@GENIA Treebank@formal@@1@S@The v-myb oncogene, carried by avian defective retroviruses, causes leukaemias in the chicken and transforms haematopoietic cells in vitro.@@@@1@22@@oe@16-12-2010 932288904@GENIA Treebank@formal@@1@S@Its normal cellular equivalent c-myb, has been shown to promote the proliferation and block the differentiation of haematopoietic cells in several experimental models and is required for fetal haematopoiesis.@@@@1@31@@oe@16-12-2010 932288905@GENIA Treebank@formal@@1@S@Two other members of the family have been cloned more recently, A-myb and B-myb, which show sequence homology with c-myb in several domains, of which the DNA binding domain as well as other regulatory domains.@@@@1@39@@oe@16-12-2010 932288906@GENIA Treebank@formal@@1@S@Both have been shown to be transcription factors.@@@@1@9@@oe@16-12-2010 932288907@GENIA Treebank@formal@@1@S@B-myb is also involved in the control of proliferation and differentiation, but, unlike c-myb, it is expressed in many cell types.@@@@1@25@@oe@16-12-2010 932288908@GENIA Treebank@formal@@1@S@The third member of the family, A-myb, shows the most restricted pattern of expression, suggesting a very specific role for this transcription factor.@@@@1@27@@oe@16-12-2010 932288909@GENIA Treebank@formal@@1@S@A-myb is expressed in a subpopulation of normal B lymphocytes activated in vivo and localised in the germinal center of peripheral lymphoid organs and is not detected at significant levels in all other mature or immature haematopoietic populations studied, including bone marrow cells, T lymphocytes, granulocytes, monocytes, either at rest or after in vitro activation.@@@@1@61@@oe@16-12-2010 932288910@GENIA Treebank@formal@@1@S@These studies indicate that A-myb plays a role during a narrow window of normal B cell differentiation.@@@@1@18@@oe@16-12-2010 932288911@GENIA Treebank@formal@@1@S@A-myb expression has also been studied in a wide range of neoplastic B cells, representing the whole spectrum of B cell differentiation.@@@@1@24@@oe@16-12-2010 932288912@GENIA Treebank@formal@@1@S@A-myb is strongly expressed in Burkitt's lymphomas (BL) and slg+ B-acute lymphoblastic leukaemias (B-ALL) and not in all other leukaemias/lymphomas tested, with the exception of a subset of CLL (about 25% of cases).@@@@1@43@@oe@16-12-2010 932288913@GENIA Treebank@formal@@1@S@It is intriguing that the A-myb genome has been localised relatively close to the c-myc gene on chromosome 8, suggesting that the c-myc translocation in BL and B-ALL may affect A-myb transcription.@@@@1@34@@oe@16-12-2010 932288914@GENIA Treebank@formal@@1@S@Studies are in progress to investigate the functional relationship between A-myb and c-myc, particularly in the context of BL cells and to determine whether A-myb is deregulated in these cells.@@@@1@32@@oe@16-12-2010 932296701@GENIA Treebank@formal@@1@S@Human neutrophils express GH-N gene transcripts and the pituitary transcription factor Pit-1b.@@@@1@13@@oe@16-12-2010 932296702@GENIA Treebank@formal@@1@S@Since GH stimulates the development and function of granulocytes, we investigated the expression of GH in granulocyte subsets.@@@@1@20@@oe@16-12-2010 932296703@GENIA Treebank@formal@@1@S@By immunocytochemistry, 25 +/- 7% of the human neutrophils were shown to express immunoreactive GH, whereas eosinophils were negative.@@@@1@23@@oe@16-12-2010 932296704@GENIA Treebank@formal@@1@S@Reversed transcription (RT)-PCR analysis demonstrated GH mRNA in neutrophils.@@@@1@13@@oe@16-12-2010 932296705@GENIA Treebank@formal@@1@S@Restriction analysis revealed that neutrophils express the GH-N gene but not the GH-V gene.@@@@1@15@@oe@16-12-2010 932296706@GENIA Treebank@formal@@1@S@Furthermore, we demonstrated by western blot analysis that neutrophils express an alternatively spliced variant of the pituitary transcription factor Pit-1, designated Pit-1b.@@@@1@25@@oe@16-12-2010 932501401@GENIA Treebank@formal@@1@S@Phospholipase C gamma 1 overexpression and activation induced by interferon beta in human T lymphocytes: an ISGF3-independent response.@@@@1@20@@oe@16-12-2010 932501402@GENIA Treebank@formal@@1@S@Interferons exert their antiviral, antiproliferative and immunoregulatory activities by stimulating the expression of several genes.@@@@1@17@@oe@16-12-2010 932501403@GENIA Treebank@formal@@1@S@Such genes disclose a common element within their promoters, defined Interferon Stimulated Response Element (ISRE), which binds a nuclear factor(s) translocated from the cytoplasm to the nucleus (ISGF3) after the binding of interferon (IFN) to the specific receptor.@@@@1@50@@oe@16-12-2010 932501404@GENIA Treebank@formal@@1@S@Here we report the induction of the synthesis and of the hydrolytic activity of phospholipase C gamma 1 (PLC gamma 1) in human T lymphocytes by IFN-beta.@@@@1@30@@oe@16-12-2010 932501405@GENIA Treebank@formal@@1@S@The increased level of PLC gamma 1 becomes evident after 90 min of IFN-beta treatment and is still detectable after 24 h.@@@@1@23@@oe@16-12-2010 932501406@GENIA Treebank@formal@@1@S@Neither the PLC gamma 1 overexpression induced by IFN nor the increased hydrolytic activity of the enzyme appear to be affected by pretreatment of the cells with the protein tyrosine kinase inhibitor genistein, which is known to prevent the association of ISGF3 components.@@@@1@45@@oe@16-12-2010 932501407@GENIA Treebank@formal@@1@S@These results suggest that in human T lymphocytes IFN-beta can activate other transcription factor(s) distinct from ISGF3 to regulate PLC gamma 1 expression.@@@@1@27@@oe@16-12-2010 932501408@GENIA Treebank@formal@@1@S@In addition, the ability of this enzyme to hydrolyse PIP2, also in the presence of genistein, implies the possibility that this enzyme can exert its hydrolytic activity independently of protein tyrosine kinase activation.@@@@1@37@@oe@16-12-2010 932623601@GENIA Treebank@formal@@1@S@Interleukin-7 upregulates the interleukin-2-gene expression in activated human T lymphocytes at the transcriptional level by enhancing the DNA binding activities of both nuclear factor of activated T cells and activator protein-1.@@@@1@32@@oe@16-12-2010 932623602@GENIA Treebank@formal@@1@S@In the present report, we studied the role of the stromal-derived cytokine interleukin-7 (IL-7) in the IL-2-gene regulation in activated T lymphocytes.@@@@1@26@@oe@16-12-2010 932623603@GENIA Treebank@formal@@1@S@Production of IL-2 requires the formation of transcription factors involved in the IL-2-gene regulation.@@@@1@15@@oe@16-12-2010 932623604@GENIA Treebank@formal@@1@S@T-cell receptor (TCR)/CD3 engagement results in the activation of nuclear factor of activated T cells (NFAT), activator protein-1 (AP-1), and nuclear factor kappaB (NFkappaB), whereas the CD28 responsive complex (CD28RC) is activated in response to the CD28 signal.@@@@1@53@@oe@16-12-2010 932623605@GENIA Treebank@formal@@1@S@Costimulation of phytohemagglutinin/anti-CD28 activated T lymphocytes with IL-7 induces a fivefold enhanced IL-2-mRNA accumulation and a 2.5-fold enhanced protein secretion.@@@@1@21@@oe@16-12-2010 932623606@GENIA Treebank@formal@@1@S@The IL-2-gene transcription rate is increased 3.4-fold, indicating that the effect of IL-7 is in part mediated at the transcriptional level.@@@@1@23@@oe@16-12-2010 932623607@GENIA Treebank@formal@@1@S@The molecular mechanisms underlying the IL-7 effect involve the upregulation of the DNA binding activity of NFAT (60%) and AP-1 (120%), without affecting the activities of NFkappaB and CD28RC, which was confirmed by transfection assays.@@@@1@44@@oe@16-12-2010 932623608@GENIA Treebank@formal@@1@S@We also show that the IL-7-induced enhancement of the AP-1-DNA binding activity is not cyclosporin A-sensitive.@@@@1@17@@oe@16-12-2010 932623609@GENIA Treebank@formal@@1@S@Since AP-1 is part of the NFAT complex, we conclude that the IL-7-signaling pathway is involved in the activation of the fos and jun proteins of which AP-1 consists.@@@@1@31@@oe@16-12-2010 932845201@GENIA Treebank@formal@@1@S@Analysis of myeloid-associated genes in human hematopoietic progenitor cells.@@@@1@10@@oe@16-12-2010 932845202@GENIA Treebank@formal@@1@S@The distribution of myeloid lineage-associated cytokine receptors and lysosomal proteins was analyzed in human CD34+ cord blood cell (CB) subsets at different stages of myeloid commitment by reverse-transcriptase polymerase chain reaction (RT-PCR).@@@@1@37@@oe@16-12-2010 932845203@GENIA Treebank@formal@@1@S@The highly specific granulomonocyte-associated lysosomal proteins myeloperoxidase (MPO) and lysozyme (LZ), as well as the transcription factor PU.1, were already detectable in the most immature CD34+Thy-1+ subset.@@@@1@34@@oe@16-12-2010 932845204@GENIA Treebank@formal@@1@S@Messenger RNA (mRNA) levels for the granulocyte-colony stimulating factor (G-CSF) receptor, granulocyte-macrophage (GM)-CSF receptor alpha subunit and tumor necrosis factor (TNF) receptors I (p55) and II (p75) were also detected in this subset in addition to c-kit and flt-3, receptors known to be expressed on progenitor cells.@@@@1@63@@oe@16-12-2010 932845205@GENIA Treebank@formal@@1@S@By contrast, the monocyte-macrophage colony stimulating factor (M-CSF) receptor was largely absent at this stage and in the CD34+Thy-1-CD45RA- subsets.@@@@1@24@@oe@16-12-2010 932845206@GENIA Treebank@formal@@1@S@The M-CSF receptor was first detectable in the myeloid-committed CD34+Thy-l-CD45RA+ subset.@@@@1@12@@oe@16-12-2010 932845207@GENIA Treebank@formal@@1@S@All other molecules studied were found to be expressed at this stage of differentiation.@@@@1@15@@oe@16-12-2010 932845208@GENIA Treebank@formal@@1@S@Different cocktails of the identified ligands were added to sorted CD34+Thy-1+ single cells.@@@@1@14@@oe@16-12-2010 932845209@GENIA Treebank@formal@@1@S@Low proliferative capacity was observed after 1 week in culture in the presence of stem cell factor (SCF) + Flt-3 ligand (FL) + G-CSF.@@@@1@29@@oe@16-12-2010 932845210@GENIA Treebank@formal@@1@S@Addition of GM-CSF to this basic cocktail consistently increased the clonogenic capacity of single CD34+Thy-1+ cells, and this effect was further enhanced (up to 72.3 +/- 4.3% on day 7) by the inclusion of TNF-alpha.@@@@1@40@@oe@16-12-2010 932845211@GENIA Treebank@formal@@1@S@In conclusion, the presence of myeloid-associated growth factor receptor transcripts in CD34+ CB subsets does not discriminate the various stages of differentiation, with the exception of the M-CSF receptor.@@@@1@32@@oe@16-12-2010 932845212@GENIA Treebank@formal@@1@S@In addition, we show that TNF-alpha is a potent costimulatory factor of the very immature CD34+Thy-1+ CB subset.@@@@1@20@@oe@16-12-2010 932934901@GENIA Treebank@formal@@1@S@Glucocorticoids and the immune function in the human immunodeficiency virus infection: a study in hypercortisolemic and cortisol-resistant patients.@@@@1@20@@oe@16-12-2010 932934902@GENIA Treebank@formal@@1@S@Immunological studies in human immunodeficiency virus (HIV)-positive patients suggest that the disease progression is accompanied by a defective production of type 1 cytokines (interleukin-2 (IL-2) and IL-12], an increased production of type 2 cytokines (IL-4, IL-6, and IL-10), and an increased production of IgE.@@@@1@58@@oe@16-12-2010 932934903@GENIA Treebank@formal@@1@S@HIV infection is also associated with activation of the hypothalamo-pituitary-adrenal axis function and increased plasma and urinary cortisol concentrations.@@@@1@20@@oe@16-12-2010 932934904@GENIA Treebank@formal@@1@S@As cortisol is involved in the physiological regulation of cytokines, a study was conducted to examine cytokine patterns in two groups of hypercortisolemic patients, one with normal sensitivity to glucocorticoids and the other with glucocorticoid resistance.@@@@1@39@@oe@16-12-2010 932934905@GENIA Treebank@formal@@1@S@Ten HIV-infected patients with normal receptor affinity to glucocorticoids (AIDS-C), 10 HIV-infected patients with low receptor affinity to glucocorticoids (AIDS-GR), and 20 healthy subjects were studied.@@@@1@33@@oe@16-12-2010 932934906@GENIA Treebank@formal@@1@S@Receptor characteristics of peripheral blood mononuclear cells were evaluated by [3H]dexamethasone binding.@@@@1@13@@oe@16-12-2010 932934907@GENIA Treebank@formal@@1@S@Serum cortisol and urinary free cortisol were measured by RIA.@@@@1@11@@oe@16-12-2010 932934908@GENIA Treebank@formal@@1@S@Serum ACTH and IgE were measured by immunoradiometric assay, and IL-2, IL-4, and IL-10 cytokines and interferon-gamma were measured by enzyme-linked immunosorbent assay.@@@@1@27@@oe@16-12-2010 932934909@GENIA Treebank@formal@@1@S@AIDS-C patients showed low IL-2 and high IL-4, IL-10, and IgE concentratios; conversely, AIDS-GR patients showed high IL-2 and low IL-4 and IgE concentrations.@@@@1@29@@oe@16-12-2010 932934910@GENIA Treebank@formal@@1@S@Thus, in HIV infection, elevated cortisol levels suppress cell-mediated immunity and stimulate humoral immunity, whereas this response is not detected in cortisol-resistant patients.@@@@1@27@@oe@16-12-2010 932934911@GENIA Treebank@formal@@1@S@These findings indicate that cortisol and its receptors are critically involved in the regulation of immune function in HIV infection.@@@@1@21@@oe@16-12-2010 933316901@GENIA Treebank@formal@@1@S@Dominant cytotoxic T lymphocyte response to the immediate-early trans-activator protein, BZLF1, in persistent type A or B Epstein-Barr virus infection.@@@@1@23@@oe@16-12-2010 933316902@GENIA Treebank@formal@@1@S@Five healthy human leukocyte antigen-B8 (HLA-B8)-positive virus carriers were studied to investigate the CD8+ cytotoxic T lymphocyte (CTL) response to an HLA-B8-restricted peptide, RAKFKQLLQ, located in the Epstein-Barr virus (EBV) immediate-early trans-activator protein, BZLF1.@@@@1@45@@oe@16-12-2010 933316903@GENIA Treebank@formal@@1@S@Of the 5 virus carriers, 4 were infected with type A and 1 with type B EBV.@@@@1@19@@oe@16-12-2010 933316904@GENIA Treebank@formal@@1@S@Using limiting-dilution analysis of peripheral blood mononuclear cells, a high RAKFKQLLQ-specific CTL precursor frequency was demonstrated after specific peptide or autologous lymphoblastoid cell line stimulation in both type A and type B EBV carriers.@@@@1@36@@oe@16-12-2010 933316905@GENIA Treebank@formal@@1@S@The RAKFKQLLQ-specific CTL precursor frequencies in all 5 persons were at least as dominant as those observed with two other EBV-associated, HLA-B8-restricted latent epitopes, FLRGRAYGL and QAKWRLQTL.@@@@1@30@@oe@16-12-2010 933316906@GENIA Treebank@formal@@1@S@These findings show that healthy virus carriers maintain a high frequency of BZLF1-specific memory T cells, potentially to control virus spread from lytically infected cells.@@@@1@27@@oe@16-12-2010 933419301@GENIA Treebank@formal@@1@S@Monochloramine inhibits phorbol ester-inducible neutrophil respiratory burst activation and T cell interleukin-2 receptor expression by inhibiting inducible protein kinase C activity.@@@@1@22@@oe@16-12-2010 933419302@GENIA Treebank@formal@@1@S@Monochloramine derivatives are long lived physiological oxidants produced by neutrophils during the respiratory burst.@@@@1@15@@oe@16-12-2010 933419303@GENIA Treebank@formal@@1@S@The effects of chemically prepared monochloramine (NH2Cl) on protein kinase C (PKC) and PKC-mediated cellular responses were studied in elicited rat peritoneal neutrophils and human Jurkat T cells.@@@@1@33@@oe@16-12-2010 933419304@GENIA Treebank@formal@@1@S@Neutrophils pretreated with NH2Cl (30-50 microM) showed a marked decrease in the respiratory burst activity induced by phorbol 12-myristate 13-acetate (PMA), which is a potent PKC activator.@@@@1@33@@oe@16-12-2010 933419305@GENIA Treebank@formal@@1@S@These cells, however, were viable and showed a complete respiratory burst upon arachidonic acid stimulation, which induces the respiratory burst by a PKC-independent mechanism.@@@@1@28@@oe@16-12-2010 933419306@GENIA Treebank@formal@@1@S@The NH2Cl-treated neutrophils showed a decrease in both PKC activity and PMA-induced phosphorylation of a 47-kDa protein, which corresponds to the cytosolic factor of NADPH oxidase, p47(phox).@@@@1@33@@oe@16-12-2010 933419307@GENIA Treebank@formal@@1@S@Jurkat T cells pretreated with NH2Cl (20-70 microM) showed a decrease in the expression of the interleukin-2 receptor alpha chain following PMA stimulation.@@@@1@26@@oe@16-12-2010 933419308@GENIA Treebank@formal@@1@S@This was also accompanied by a decrease in both PKC activity and nuclear transcription factor-kappaB activation, also without loss of cell viability.@@@@1@24@@oe@16-12-2010 933419309@GENIA Treebank@formal@@1@S@These results show that NH2Cl inhibits PKC-mediated cellular responses through inhibition of the inducible PKC activity.@@@@1@17@@oe@16-12-2010 933472301@GENIA Treebank@formal@@1@S@HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor kappa B [see comments]@@@@1@18@@oe@16-12-2010 933472302@GENIA Treebank@formal@@1@S@The HIV-1 accessory gene product Vpr can influence viral pathogenesis by affecting viral replication as well as host cell transcription and proliferation.@@@@1@23@@oe@16-12-2010 933472303@GENIA Treebank@formal@@1@S@We have investigated the effects of Vpr on host cell activation and confirm that it influences cellular proliferation.@@@@1@19@@oe@16-12-2010 933472304@GENIA Treebank@formal@@1@S@However, we have also found that Vpr modulates T-cell receptor (TCR)-triggered apoptosis in a manner similar to that of glucocorticoids.@@@@1@25@@oe@16-12-2010 933472305@GENIA Treebank@formal@@1@S@In the absence of TCR-mediated activation, Vpr induces apoptosis whereas in its presence, Vpr interrupts the expected induction of apoptosis.@@@@1@23@@oe@16-12-2010 933472306@GENIA Treebank@formal@@1@S@This regulation of apoptosis is linked to Vpr suppression of NF-kappa B activity via the induction of I kappa B, an inhibitor of NF-kappa B.@@@@1@27@@oe@16-12-2010 933472307@GENIA Treebank@formal@@1@S@Further, Vpr suppresses expression of IL-2, IL-10, IL-12, TNF alpha and IL-4, all of which are NF-kappa B-dependent.@@@@1@24@@oe@16-12-2010 933472308@GENIA Treebank@formal@@1@S@The effects of Vpr could be reversed by RU486.@@@@1@10@@oe@16-12-2010 933472309@GENIA Treebank@formal@@1@S@Our finding that Vpr can regulate NF-kappa B supports the hypothesis that some aspects of viral pathogenesis are the consequence of cell dysregulation by Vpr.@@@@1@26@@oe@16-12-2010 933935601@GENIA Treebank@formal@@1@S@Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans.@@@@1@17@@oe@16-12-2010 933935602@GENIA Treebank@formal@@1@S@Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa lipocalin first identified as a protein stored in specific granules of the human neutrophil.@@@@1@24@@oe@16-12-2010 933935603@GENIA Treebank@formal@@1@S@The protein is believed to bind small lipophilic substances such as bacterial derived formylpeptides and lipopolysaccharides (LPS) and might function as a modulator of inflammation.@@@@1@28@@oe@16-12-2010 933935604@GENIA Treebank@formal@@1@S@To characterize the regulation of NGAL further, we have cloned and sequenced a 5869-bp region of the NGAL gene including 1695 bp of the 5' nontranscribed region and a 3696-bp coding region encompassing seven exons and six introns.@@@@1@40@@oe@16-12-2010 933935605@GENIA Treebank@formal@@1@S@The transcriptional start sites were identified by an RNase protection assay.@@@@1@12@@oe@16-12-2010 933935606@GENIA Treebank@formal@@1@S@The NGAL gene is highly homologous to the mouse gene 24p3.@@@@1@12@@oe@16-12-2010 933935607@GENIA Treebank@formal@@1@S@NGAL was expressed in bone marrow and in tissues that are prone to exposure to microorganisms.@@@@1@17@@oe@16-12-2010 933935608@GENIA Treebank@formal@@1@S@Potential cis-acting elements were identified in the promoter region of the NGAL gene by computer analysis and include binding sites for CTF/CBP, the hematopoietic transcription factors GATA-1 and PU.1, and the LPS-inducible factor NF-kappa B.@@@@1@38@@oe@16-12-2010 934115101@GENIA Treebank@formal@@1@S@Purification and characterization of the human SR 31747A-binding protein.@@@@1@10@@oe@16-12-2010 934115102@GENIA Treebank@formal@@1@S@A nuclear membrane protein related to yeast sterol isomerase.@@@@1@10@@oe@16-12-2010 934115103@GENIA Treebank@formal@@1@S@SR 31747A, defined as a sigma ligand, is a novel immunosuppressive agent that blocks proliferation of human and mouse lymphocytes.@@@@1@23@@oe@16-12-2010 934115104@GENIA Treebank@formal@@1@S@Using a radiolabeled chemical probe, we here purified a target of SR 31747A and called it SR 31747A-binding protein (SR-BP).@@@@1@24@@oe@16-12-2010 934115105@GENIA Treebank@formal@@1@S@Purified SR-BP retained its binding properties and migrated on SDS-polyacrylamide gel as a Mr 28,000 protein.@@@@1@17@@oe@16-12-2010 934115106@GENIA Treebank@formal@@1@S@Cloning of the cDNA encoding human SR-BP shows an open reading frame for a 223-amino acid protein, which is homologous to the recently cloned sigma 1 receptor.@@@@1@29@@oe@16-12-2010 934115107@GENIA Treebank@formal@@1@S@Interestingly, the deduced amino acid sequence was found to be related to fungal C8-C7 sterol isomerase, encoded by the ERG2 gene.@@@@1@24@@oe@16-12-2010 934115108@GENIA Treebank@formal@@1@S@The ERG2 gene product has been identified recently as the molecular target of SR 31747A that mediates antiproliferative effects of the drug in yeast.@@@@1@25@@oe@16-12-2010 934115109@GENIA Treebank@formal@@1@S@Northern blot analysis of SR-BP gene expression revealed a single transcript of 2 kilobases which was widely expressed among organs, with the highest abundance in liver and the lowest abundance in brain.@@@@1@34@@oe@16-12-2010 934115110@GENIA Treebank@formal@@1@S@Subcellular localization analysis in various cells, using a specific monoclonal antibody raised against SR-BP, demonstrated that this protein was associated with the nuclear envelope.@@@@1@27@@oe@16-12-2010 934115111@GENIA Treebank@formal@@1@S@When studying the binding of SR 31747A on membranes from yeast expressing SR-BP, we found a pharmacological profile of sigma 1 receptors; binding was displaced by (+)-pentazocine, haloperidol, and (+)-SKF 10,047, with (+)-SKF 10, 047 being a more potent competitor than (-)-SKF 10,047.@@@@1@48@@oe@16-12-2010 934115112@GENIA Treebank@formal@@1@S@Scatchard plot analysis revealed Kd values of 7.1 nM and 0.15 nM for (+)-pentazocine and SR 31747A, respectively, indicating an affinity of SR-BP 50-fold higher for SR 31747A than for pentazocine.@@@@1@34@@oe@16-12-2010 934115113@GENIA Treebank@formal@@1@S@Additionally, we showed that pentazocine, a competitive inhibitor of SR 31747A binding, also prevents the immunosuppressive effect of SR 31747A.@@@@1@24@@oe@16-12-2010 934115114@GENIA Treebank@formal@@1@S@Taken together, these findings strongly suggest that SR-BP represents the molecular target for SR 31747A in mammalian tissues, which could be critical for T cell proliferation.@@@@1@29@@oe@16-12-2010 934119301@GENIA Treebank@formal@@1@S@The tax protein of human T-cell leukemia virus type 1 mediates the transactivation of the c-sis/platelet-derived growth factor-B promoter through interactions with the zinc finger transcription factors Sp1 and NGFI-A/Egr-1.@@@@1@31@@oe@16-12-2010 934119302@GENIA Treebank@formal@@1@S@Transcriptional up-regulation of the c-sis/platelet-derived growth factor-B (PDGF-B) proto-oncogene by the Tax protein of human T-cell leukemia virus type 1 has been implicated as one possible mechanism of cellular transformation by human T-cell leukemia virus type 1.@@@@1@40@@oe@16-12-2010 934119303@GENIA Treebank@formal@@1@S@In previous work, we identified an essential site in the c-sis/PDGF-B promoter, Tax-responsive element 1 (TRE1), necessary for transactivation by Tax.@@@@1@27@@oe@16-12-2010 934119304@GENIA Treebank@formal@@1@S@We also identified Sp1, Sp3, and NGFI-A/Egr-1 as the primary nuclear transcription factors binding to TRE1 which mediate Tax responsiveness.@@@@1@23@@oe@16-12-2010 934119305@GENIA Treebank@formal@@1@S@In the present work, we have investigated the mechanism(s) whereby Tax transactivates the c-sis/PDGF-B proto-oncogene.@@@@1@20@@oe@16-12-2010 934119306@GENIA Treebank@formal@@1@S@In vitro transcription assays showed that Tax was able to significantly increase the transcriptional activity of a template containing the -257 to +74 region of the c-sis/PDGF-B promoter.@@@@1@29@@oe@16-12-2010 934119307@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assay analysis showed that Tax increased the DNA binding activity of both Sp1 and NGFI-A/Egr-1 using a TRE1 probe.@@@@1@23@@oe@16-12-2010 934119308@GENIA Treebank@formal@@1@S@Analysis of Tax mutants showed that two mutants, IEXC29S and IEXL320G, were unable to significantly transactivate the c-sis/PDGF-B promoter.@@@@1@22@@oe@16-12-2010 934119309@GENIA Treebank@formal@@1@S@Finally, co-immunoprecipitation analysis revealed that Tax is able to stably bind to both Sp1 and NGFI-A/Egr-1.@@@@1@18@@oe@16-12-2010 934119310@GENIA Treebank@formal@@1@S@Interestingly, co-immunoprecipitation analysis also revealed that Tax mutant IEXC29S is unable to interact with NGFI-A/Egr-1, whereas Tax mutant IEXL320G is able to interact with NGFI-A/Egr-1.@@@@1@28@@oe@16-12-2010 934175601@GENIA Treebank@formal@@1@S@Induction of endothelial cell surface adhesion molecules by tumor necrosis factor is blocked by protein tyrosine phosphatase inhibitors: role of the nuclear transcription factor NF-kappa B.@@@@1@28@@oe@16-12-2010 934175602@GENIA Treebank@formal@@1@S@Recent studies from our laboratory have indicated that protein tyrosine phosphatase (PTPase) inhibitors can down-modulate the tumor necrosis factor (TNF)-mediated activation of the nuclear transcription factor NF-kappa B in ML-1a, a monocytic cell line (Singh and Aggarwal, J. Biol. Chem. 1995: 270: 10631).@@@@1@55@@oe@16-12-2010 934175603@GENIA Treebank@formal@@1@S@Since TNF is one of the major inducers of various adhesion molecules in human endothelial cells and their expression is known to require the activation of NF-kappa B, we examined the effect of PTPase inhibitors on the TNF-mediated induction of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1.@@@@1@67@@oe@16-12-2010 934175604@GENIA Treebank@formal@@1@S@Like ML-1a, human dermal microvessel endothelial cells (MVEC) treated with TNF rapidly activated (within 30 min) NF-kappa B; this effect was completely abolished by co-treatment with phenylarsine oxide (PAO), a specific inhibitor of PTPase.@@@@1@44@@oe@16-12-2010 934175605@GENIA Treebank@formal@@1@S@The induction of ICAM-1, VCAM-1, and ELAM-1 by TNF in MVEC occurred within 6 h and was also completely down-regulated by PAO in a dose-dependent manner.@@@@1@29@@oe@16-12-2010 934175606@GENIA Treebank@formal@@1@S@PAO was found to be effective even when added 3 h after TNF, suggesting a rapid mode of action of this inhibitor.@@@@1@24@@oe@16-12-2010 934175607@GENIA Treebank@formal@@1@S@Besides PAO, other inhibitors of PTPase, including pervanadate and diamide, also blocked TNF-dependent NF-kappa B activation and induction of all the three adhesion proteins.@@@@1@28@@oe@16-12-2010 934175608@GENIA Treebank@formal@@1@S@Consistent with these results, the attachment of monocytes to MVEC was also blocked by the PTPase inhibitors.@@@@1@19@@oe@16-12-2010 934175609@GENIA Treebank@formal@@1@S@Thus, overall, our results demonstrate that a PTPase is involved either directly or indirectly in the pathway leading to the induction of endothelial cell adhesion molecules by TNF.@@@@1@31@@oe@16-12-2010 934175610@GENIA Treebank@formal@@1@S@Because of their role in cell adhesion, PTPase may provide a novel target of drug development for treatment of inflammation, atherogenesis, and tumor metastasis.@@@@1@28@@oe@16-12-2010 934187701@GENIA Treebank@formal@@1@S@The spatial distribution of human immunoglobulin genes within the nucleus: evidence for gene topography independent of cell type and transcriptional activity.@@@@1@23@@oe@16-12-2010 934187702@GENIA Treebank@formal@@1@S@The three-dimensional positioning of immunoglobulin (Ig) genes within the nucleus of human cells was investigated using in situ hybridization and confocal microscopy.@@@@1@25@@oe@16-12-2010 934187703@GENIA Treebank@formal@@1@S@The visualization of heavy and light chain genes in B-lymphoid cells showed that the three Ig genes are differentially and nonrandomly distributed in different nuclear subvolumes: the kappa genes were found to be preferentially confined to an outer nuclear volume, whereas the gamma and lambda genes consistently occupied more central positions within the nucleus, the lambda genes being more interior when compared with the gamma genes.@@@@1@70@@oe@16-12-2010 934187704@GENIA Treebank@formal@@1@S@The data further show that these overall topographical distributions are independent of gene transcriptional activity and are conserved in different cell types.@@@@1@23@@oe@16-12-2010 934187705@GENIA Treebank@formal@@1@S@Although subtle gene movements within those defined topographical regions cannot be excluded by this study, the results indicate that tissue specificity of gene expression is not accompanied by drastic changes in gene nuclear topography, rather suggesting that gene organization within the nucleus may be primarily dependent on structural constraints imposed on the respective chromosomes.@@@@1@58@@oe@16-12-2010 934218601@GENIA Treebank@formal@@1@S@Monocytic differentiation of HL-60 promyelocytic leukemia cells correlates with the induction of Bcl-xL.@@@@1@14@@oe@16-12-2010 934218602@GENIA Treebank@formal@@1@S@Treatment of human promyelocytic leukemia HL-60 cells with phorbol esters ultimately induces the differentiation of these cells along the monocyte/macrophage lineage, whereas treatment with retinoic acid or DMSO induces granulocytic/neutrophillic differentiation.@@@@1@33@@oe@16-12-2010 934218603@GENIA Treebank@formal@@1@S@In this study, we demonstrate the disparate fates of HL-60 cells treated with the phorbol ester 12,13-phorbol dibutyric acid (PDBu) or DMSO.@@@@1@26@@oe@16-12-2010 934218604@GENIA Treebank@formal@@1@S@After DMSO treatment, HL-60 cells eventually died via apoptosis, whereas the viability of PDBu-treated cells was not affected during the same interval.@@@@1@25@@oe@16-12-2010 934218605@GENIA Treebank@formal@@1@S@The levels of the apoptosis effector proteins Bak and Bad were enhanced, whereas there was a slight down-regulation of the apoptosis suppressor protein Bcl-2 after treatment of the cells with PDBu and DMSO.@@@@1@35@@oe@16-12-2010 934218606@GENIA Treebank@formal@@1@S@Treatment with DMSO resulted in the elevation of the apoptosis effector Bax, whereas treatment with PDBu did not significantly alter the levels of this protein.@@@@1@27@@oe@16-12-2010 934218607@GENIA Treebank@formal@@1@S@However, treatment of HL-60 cells with PDBu induced the rapid expression of the apoptosis suppressor protein Bcl-xL, whereas the expression of this protein remained unaltered in DMSO-treated cells.@@@@1@31@@oe@16-12-2010 934218608@GENIA Treebank@formal@@1@S@The generality of this finding was confirmed by the induction of Bcl-xL in human myeloid U-937 cells, human peripheral blood monocytes exposed to phorbol ester, and mouse thioglycollate-activated and resident peritoneal macrophages.@@@@1@35@@oe@16-12-2010 934218609@GENIA Treebank@formal@@1@S@PDBu-treated HL-60 cells remained viable for 7 days and thereafter began to die via apoptosis, with a concomitant down-regulation of Bcl-xL.@@@@1@23@@oe@16-12-2010 934218610@GENIA Treebank@formal@@1@S@In conclusion, we propose that Bcl-xL expression is associated with differentiation and survival of hematopoietic cells along the monocyte/macrophage lineage.@@@@1@22@@oe@16-12-2010 934321001@GENIA Treebank@formal@@1@S@Transcriptional activation of the vascular cell adhesion molecule-1 gene in T lymphocytes expressing human T-cell leukemia virus type 1 Tax protein.@@@@1@22@@oe@16-12-2010 934321002@GENIA Treebank@formal@@1@S@Recruitment and extravasation of T cells through the blood-brain barrier are favored by adhesion molecule-mediated interactions of circulating T cells with endothelial cells.@@@@1@24@@oe@16-12-2010 934321003@GENIA Treebank@formal@@1@S@Since a common pathological finding in human T-cell leukemia virus type 1 (HTLV-1)-associated diseases is the infiltration of HTLV-1-infected T lymphocytes into various organs, we have looked for the profile of adhesion molecules expressed by HTLV-1-transformed T cells.@@@@1@43@@oe@16-12-2010 934321004@GENIA Treebank@formal@@1@S@Flow cytometry analysis indicated that these cells were expressing high levels of vascular cell adhesion molecule 1 (VCAM-1 [CD106]), a 110-kDa member of the immunoglobulin gene superfamily, first identified on endothelial cells stimulated with inflammatory cytokines.@@@@1@43@@oe@16-12-2010 934321005@GENIA Treebank@formal@@1@S@This adhesion molecule was also expressed by T cells obtained from one patient with HTLV-1-associated myelopathy/tropical spastic paraparesis but not by activated T cells isolated from one normal blood donor.@@@@1@31@@oe@16-12-2010 934321006@GENIA Treebank@formal@@1@S@The role of the viral trans-activator Tax protein in the induction of VCAM-1 was first indicated by the detection of this adhesion molecule on Jurkat T-cell clones stably expressing the tax gene.@@@@1@33@@oe@16-12-2010 934321007@GENIA Treebank@formal@@1@S@The effect of Tax on VCAM-1 gene transcription was next confirmed in JPX-9 cells, a subclone of Jurkat cells, carrying the tax sequences under the control of an inducible promoter.@@@@1@33@@oe@16-12-2010 934321008@GENIA Treebank@formal@@1@S@Furthermore, deletion and mutation analyses of the VCAM-1 promoter performed with chloramphenicol acetyltransferase constructs revealed that Tax was trans activating the VCAM-1 promoter via two NF-kappaB sites present at bp -72 and -57 in the VCAM-1 gene promoter, with both of them being required for the Tax-induced expression of this adhesion molecule.@@@@1@55@@oe@16-12-2010 934321009@GENIA Treebank@formal@@1@S@Finally, gel mobility shift assays demonstrated the nuclear translocation of proteins specifically bound to these two NF-kappaB motifs, confirming that VCAM-1 was induced on Tax-expressing cells in a kappaB-dependent manner.@@@@1@33@@oe@16-12-2010 934321010@GENIA Treebank@formal@@1@S@Collectively, these results therefore suggest that the exclusive Tax-induced expression of VCAM-1 on T cells may represent a pivotal event in the progression of HTLV-1-associated diseases.@@@@1@28@@oe@16-12-2010 934321301@GENIA Treebank@formal@@1@S@Epstein-Barr virus EBNA3C represses Cp, the major promoter for EBNA expression, but has no effect on the promoter of the cell gene CD21.@@@@1@26@@oe@16-12-2010 934321302@GENIA Treebank@formal@@1@S@EBNA3C is a potent repressor of transcription when bound to DNA as a fusion with the DNA binding domain (DBD) of GALA.@@@@1@25@@oe@16-12-2010 934321303@GENIA Treebank@formal@@1@S@A survey of promoters has revealed that the wild-type, unfused EBNA3C can specifically repress expression from reporter plasmids containing the Epstein-Barr virus Cp latency-associated promoter.@@@@1@27@@oe@16-12-2010 934321304@GENIA Treebank@formal@@1@S@Repression of Cp activity required amino acids 207 to 368, which encompasses a region resembling a basic DBD adjacent to a leucine zipper DNA binding motif and a site which binds to the cellular factor CBF1/RBP-Jkappa.@@@@1@38@@oe@16-12-2010 934321305@GENIA Treebank@formal@@1@S@However, amino acids 207 to 368 are dispensable when the protein is bound to DNA as a fusion with the GAL4 DBD, thus implicating this region in DNA binding.@@@@1@32@@oe@16-12-2010 934321306@GENIA Treebank@formal@@1@S@Mutation of the CBF1/RBP-Jkappa binding site in EBNA3C abrogated repression, strongly suggesting that CBF1/RBP-Jkappa is necessary for targeting the viral protein to Cp.@@@@1@25@@oe@16-12-2010 934321307@GENIA Treebank@formal@@1@S@Consistent with this result, mutation of the EBNA2 response element (a CBF1/RBP-Jkappa binding site) in Cp also prevented significant repression.@@@@1@24@@oe@16-12-2010 934321308@GENIA Treebank@formal@@1@S@In addition, amino acids 346 to 543, which were previously defined as important for the repressor activity of the GAL4-EBNA3C fusion proteins, also appear to be necessary for the repression of Cp.@@@@1@36@@oe@16-12-2010 934321309@GENIA Treebank@formal@@1@S@Since repression by these fusions was not observed in all cell types, it seems likely that EBNA3C either depends on a corepressor which may interact with amino acids 346 to 543 or is modified in a cell-specific manner in order to repress.@@@@1@44@@oe@16-12-2010 934321310@GENIA Treebank@formal@@1@S@These data are consistent with EBNA3C contributing to the regulation of EBNA expression in latently infected B cells through CBF1/RBP-Jkappa and another factor, but this need not directly involve EBNA2.@@@@1@32@@oe@16-12-2010 934321311@GENIA Treebank@formal@@1@S@Finally, although it has been reported that EBNA3C can upregulate CD21 in some B cells, we were unable to demonstrate any effect of EBNA3C on reporter plasmids which contain the CD21 promoter.@@@@1@35@@oe@16-12-2010 934323101@GENIA Treebank@formal@@1@S@Late gene expression from the Epstein-Barr virus BcLF1 and BFRF3 promoters does not require DNA replication in cis.@@@@1@19@@oe@16-12-2010 934323102@GENIA Treebank@formal@@1@S@Late gene expression follows and is dependent upon lytic replication of the viral genome.@@@@1@15@@oe@16-12-2010 934323103@GENIA Treebank@formal@@1@S@Although experimental evidence is lacking, lytic viral DNA replication is believed to remove modifications or binding factors from the genome which serve to repress late gene expression during latency or the early lytic cycle.@@@@1@36@@oe@16-12-2010 934323104@GENIA Treebank@formal@@1@S@We have developed a reporter assay to begin characterizing the mechanisms that regulate late gene expression in Epstein-Barr virus (EBV).@@@@1@23@@oe@16-12-2010 934323105@GENIA Treebank@formal@@1@S@In this model system, the activities of late promoter-reporter fusions are measured following transient transfection into tissue culture cells expressing EBV during different stages of the lytic cycle.@@@@1@30@@oe@16-12-2010 934323106@GENIA Treebank@formal@@1@S@This system faithfully recapitulates late expression patterns from the endogenous virus, implicating specific cis-active sequences in the control of late gene expression.@@@@1@24@@oe@16-12-2010 934323107@GENIA Treebank@formal@@1@S@In addition, these promoters respond only indirectly to the viral immediate-early transactivator, ZEBRA.@@@@1@16@@oe@16-12-2010 934323108@GENIA Treebank@formal@@1@S@This indirect response is mediated by other viral or virally induced activities downstream of ZEBRA in the lytic cascade.@@@@1@20@@oe@16-12-2010 934323109@GENIA Treebank@formal@@1@S@In this system, late gene expression is sensitive to inhibitors of the viral DNA polymerase such as phosphonoacetic acid, although the reporters lack a eukaryotic origin of replication and are not replicated under the assay conditions.@@@@1@39@@oe@16-12-2010 934323110@GENIA Treebank@formal@@1@S@Thus, replication of the transcriptional template is not a prerequisite for expression with late kinetics, a finding inconsistent with the current models which posit a cis-active relationship between lytic EBV DNA replication and late gene expression.@@@@1@39@@oe@16-12-2010 934323111@GENIA Treebank@formal@@1@S@Rather, analysis of this system has revealed a trans relationship between late gene expression and viral DNA replication and highlights the indirect and complex link between these two events.@@@@1@31@@oe@16-12-2010 934340601@GENIA Treebank@formal@@1@S@Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.@@@@1@19@@oe@16-12-2010 934340602@GENIA Treebank@formal@@1@S@Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types.@@@@1@21@@oe@16-12-2010 934340603@GENIA Treebank@formal@@1@S@Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases.@@@@1@31@@oe@16-12-2010 934340604@GENIA Treebank@formal@@1@S@We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation.@@@@1@25@@oe@16-12-2010 934340605@GENIA Treebank@formal@@1@S@This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT).@@@@1@51@@oe@16-12-2010 934340606@GENIA Treebank@formal@@1@S@Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1.@@@@1@49@@oe@16-12-2010 934340607@GENIA Treebank@formal@@1@S@Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc.@@@@1@24@@oe@16-12-2010 934340608@GENIA Treebank@formal@@1@S@Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells.@@@@1@34@@oe@16-12-2010 934340609@GENIA Treebank@formal@@1@S@We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp.@@@@1@54@@oe@16-12-2010 934340610@GENIA Treebank@formal@@1@S@In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants.@@@@1@20@@oe@16-12-2010 934436501@GENIA Treebank@formal@@1@S@Suppression of nuclear factor kappa B and CD18-mediated leukocyte adhesion to the corneal endothelium by dexamethasone.@@@@1@17@@oe@16-12-2010 934436502@GENIA Treebank@formal@@1@S@PURPOSE: To demonstrate that leukocyte adhesion to cultured corneal endothelial cells is mediated by the CD18 antigen, and to determine whether dexamethasone directly suppresses adhesion by inhibiting activation of nuclear factor kappa B (NFkappaB).@@@@1@39@@oe@16-12-2010 934436503@GENIA Treebank@formal@@1@S@METHODS: Cultured bovine corneal endothelium was stimulated for 6 hours by 40 micron/ml tumor necrosis factor alpha (TNFalpha).@@@@1@22@@oe@16-12-2010 934436504@GENIA Treebank@formal@@1@S@Dexamethasone was added 1 hour before TNFalpha stimulation in the dexamethasone group.@@@@1@13@@oe@16-12-2010 934436505@GENIA Treebank@formal@@1@S@After stimulation, neutrophils separated from a healthy human volunteer were added with or without anti-CD18 antibody.@@@@1@18@@oe@16-12-2010 934436506@GENIA Treebank@formal@@1@S@The culture plate was settled for 15 minutes at 37 degrees C, and then neutrophils were activated by N-formyl-methionyl-leucyl-phenylalanine for 5 minutes.@@@@1@24@@oe@16-12-2010 934436507@GENIA Treebank@formal@@1@S@Nonadherent neutrophils were removed by sealing and inverting the culture well.@@@@1@12@@oe@16-12-2010 934436508@GENIA Treebank@formal@@1@S@The intracellular localization of NFkappaB after TNFalpha simulation was determined by confocal immunocytochemistry using an anti-p65 antibody.@@@@1@18@@oe@16-12-2010 934436509@GENIA Treebank@formal@@1@S@RESULTS: Neutrophil adhesion to cultured corneal endothelial cells increased significantly on exposure to TNFalpha (451.4+/-45.4 cells/mm2, n = 16) compared to control (156.7+/-27.3 cells/mm2, n = 16, P < 0.01).@@@@1@39@@oe@16-12-2010 934436510@GENIA Treebank@formal@@1@S@This increased adhesion was suppressed by the addition of anti-CD18 antibody (157.6+/-25.1 cells/mm2, n = 8, P < 0.01) and by pretreatment with 10(-7) M dexamethasone (207.9+/-31.5 cells/mm2, n = 10, P < 0.01).@@@@1@43@@oe@16-12-2010 934436511@GENIA Treebank@formal@@1@S@Immunocytochemistry 60 minutes after stimulation revealed that NFkappaB was located in the cytoplasm in unstimulated cells; however, the addition of TNFalpha caused NFkappaB to translocate into the nucleus.@@@@1@31@@oe@16-12-2010 934436512@GENIA Treebank@formal@@1@S@Pretreatment with dexamethasone tapered NFkappaB translocation into the nucleus.@@@@1@10@@oe@16-12-2010 934436513@GENIA Treebank@formal@@1@S@CONCLUSIONS: Leukocyte adhesion to the corneal endothelium was shown to be mediated by CD18 expressed on activated leukocytes.@@@@1@20@@oe@16-12-2010 934436514@GENIA Treebank@formal@@1@S@Pretreatment of the endothelium with dexamethasone inhibited leukocyte adhesion; this may be due in part to the suppression of NFkappaB entry into the nucleus.@@@@1@26@@oe@16-12-2010 934458901@GENIA Treebank@formal@@1@S@Stable transfection of U937 cells with sense or antisense RXR-alpha cDNA suggests a role for RXR-alpha in the control of monoblastic differentiation induced by retinoic acid and vitamin D.@@@@1@30@@oe@16-12-2010 934458902@GENIA Treebank@formal@@1@S@Although retinoic acid (RA) has been known for many years to be a modulating agent that plays a role in generating both granulocytes and monocytes, the molecular mechanism underlying this role has not been defined in the monoblast lineage.@@@@1@43@@oe@16-12-2010 934458903@GENIA Treebank@formal@@1@S@In particular, the part played by the retinoid X receptors (RXRs), which are members of the steroid/thyroid hormone nuclear receptor family, has not been explored.@@@@1@31@@oe@16-12-2010 934458904@GENIA Treebank@formal@@1@S@In this study, therefore, the human monoblastic leukemia cell line U937 has been used as a model system to investigate the role of one of the RXRs, RXR-alpha, in monoblast differentiation.@@@@1@36@@oe@16-12-2010 934458905@GENIA Treebank@formal@@1@S@RXR-alpha mRNA was present in untreated U937 cells, and levels increased after induction of differentiation with phorbol ester.@@@@1@20@@oe@16-12-2010 934458906@GENIA Treebank@formal@@1@S@The same was found for RXR-beta mRNA.@@@@1@8@@oe@16-12-2010 934458907@GENIA Treebank@formal@@1@S@Using plasmids containing sense or antisense RXR-alpha sequences under the control of an inducible promoter, we generated stably transfected cell lines which expressed either increased or decreased levels of RXR-alpha, respectively.@@@@1@34@@oe@16-12-2010 934458908@GENIA Treebank@formal@@1@S@The sense cell lines (U alpha S and its clonal derivative alpha G2S) showed increased sensitivity to RA, while the antisense cell lines (U alpha A and its clonal derivative alpha B5A) showed decreased sensitivity to RA, as demonstrated by growth inhibition and by regulation of an RA-responsive reporter gene.@@@@1@57@@oe@16-12-2010 934458909@GENIA Treebank@formal@@1@S@Both U alpha A and alpha B5A also failed to respond to another modulating agent, 1 alpha,25-dihydroxycholecalciferol (DHCC), but only U alpha S and not alpha G2S showed an enhanced response to DHCC.@@@@1@38@@oe@16-12-2010 934458910@GENIA Treebank@formal@@1@S@The combination of RA and DHCC together inhibited growth of both sense and antisense cell lines.@@@@1@17@@oe@16-12-2010 934458911@GENIA Treebank@formal@@1@S@In addition, alpha G2S exhibited increased expression of CD11b and CD54, while alpha B5A cells showed increased expression of CD102, suggesting that RXR-alpha has a role in regulating expression of cell adhesion molecules in U937 cells.@@@@1@40@@oe@16-12-2010 934458912@GENIA Treebank@formal@@1@S@These results demonstrate that RXR-alpha has a role in mediating growth inhibition and cell adhesion during myelomonocytic differentiation, and suggest that different species of heterodimers involving RXR-alpha may control the acquisition of different features of mature monocyte/macrophage function.@@@@1@40@@oe@16-12-2010 934545601@GENIA Treebank@formal@@1@S@B-lymphoblastoid cell lines from multiple sclerosis patients and a healthy control producing a putative new human retrovirus and Epstein-Barr virus.@@@@1@21@@oe@16-12-2010 934545602@GENIA Treebank@formal@@1@S@On several occasions we have observed retrovirus-like particles (RVLPs) by transmission electron microscopy (EM) of cultured T cells from a patient with MS.@@@@1@28@@oe@16-12-2010 934545603@GENIA Treebank@formal@@1@S@Later we established spontaneously formed B-lymphoblastoid cell lines (LCLs) from a patient with an MS-like disease and from another patient with MS who had a reactivated Epstein-Barr virus (EBV) infection.@@@@1@35@@oe@16-12-2010 934545604@GENIA Treebank@formal@@1@S@Both LCLs were found by EM to produce RVLP and EBV particles.@@@@1@13@@oe@16-12-2010 934545605@GENIA Treebank@formal@@1@S@Reverse transcriptase (RT) assays were positive in purified viral material from both LCLs.@@@@1@16@@oe@16-12-2010 934545606@GENIA Treebank@formal@@1@S@To substantiate these findings we initiated an intensified culturing procedure and were able to establish LCLs from 5 out of 21 consecutive MS patients and 1 out of 13 consecutive healthy controls.@@@@1@33@@oe@16-12-2010 934545607@GENIA Treebank@formal@@1@S@All LCLs were found to produce both RVLP and EBV particles by EM.@@@@1@14@@oe@16-12-2010 934545608@GENIA Treebank@formal@@1@S@Whether the putative new retrovirus(es) and EBV have any causal relationship to MS is still not known, but the findings support this possibility.@@@@1@28@@oe@16-12-2010 934810401@GENIA Treebank@formal@@1@S@Helenalin, an anti-inflammatory sesquiterpene lactone from Arnica, selectively inhibits transcription factor NF-kappaB [see comments]@@@@1@18@@oe@16-12-2010 934810402@GENIA Treebank@formal@@1@S@Alcoholic extracts prepared form Arnicae flos, the collective name for flowerheads from Arnica montana and A. chamissonis ssp. foliosa, are used therapeutically as anti-inflammatory remedies.@@@@1@28@@oe@16-12-2010 934810403@GENIA Treebank@formal@@1@S@The active ingredients mediating the pharmacological effect are mainly sesquiterpene lactones, such as helenalin, 11alpha,13-dihydrohelenalin, chamissonolid and their ester derivatives.@@@@1@24@@oe@16-12-2010 934810404@GENIA Treebank@formal@@1@S@While these compounds affect various cellular processes, current data do not fully explain how sesquiterpene lactones exert their anti-inflammatory effect.@@@@1@22@@oe@16-12-2010 934810405@GENIA Treebank@formal@@1@S@We show here that helenalin, and, to a much lesser degree, 11alpha,13-dihydrohelenalin and chamissonolid, inhibit activation of transcription factor NF-kappaB.@@@@1@25@@oe@16-12-2010 934810406@GENIA Treebank@formal@@1@S@This difference in efficacy, which correlates with the compounds' anti-inflammatory potency in vivo, may be explained by differences in structure and conformation.@@@@1@26@@oe@16-12-2010 934810407@GENIA Treebank@formal@@1@S@NF-kappaB, which resides in an inactive, cytoplasmic complex in unstimulated cells, is activated by phosphorylation and degradation of its inhibitory subunit, IkappaB.@@@@1@27@@oe@16-12-2010 934810408@GENIA Treebank@formal@@1@S@Helenalin inhibits NF-kappaB activation in response to four different stimuli in T-cells, B-cells and epithelial cells and abrogates kappaB-driven gene expression.@@@@1@23@@oe@16-12-2010 934810409@GENIA Treebank@formal@@1@S@This inhibition is selective, as the activity of four other transcription factors, Oct-1, TBP, Sp1 and STAT 5 was not affected.@@@@1@26@@oe@16-12-2010 934810410@GENIA Treebank@formal@@1@S@We show that inhibition is not due to a direct modification of the active NF-kappaB heterodimer.@@@@1@17@@oe@16-12-2010 934810411@GENIA Treebank@formal@@1@S@Rather, helenalin modifies the NF-kappaB/IkappaB complex, preventing the release of IkappaB.@@@@1@14@@oe@16-12-2010 934810412@GENIA Treebank@formal@@1@S@These data suggest a molecular mechanism for the anti-inflammatory effect of sesquiterpene lactones, which differs from that of other nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and acetyl salicylic acid.@@@@1@33@@oe@16-12-2010 934831401@GENIA Treebank@formal@@1@S@Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta.@@@@1@12@@oe@16-12-2010 934831402@GENIA Treebank@formal@@1@S@In many chronic inflammatory disorders, glucocorticoid (GC) insensitivity is a challenging clinical problem associated with life-threatening disease progression.@@@@1@22@@oe@16-12-2010 934831403@GENIA Treebank@formal@@1@S@The molecular basis of GC insensitivity, however, is unknown.@@@@1@12@@oe@16-12-2010 934831404@GENIA Treebank@formal@@1@S@Alternative splicing of the GC receptor (R) pre-messenger RNA generates a second GCR, termed GCR-beta, which does not bind GCs but antagonizes the transactivating activity of the classic GCR, termed GCR-alpha.@@@@1@37@@oe@16-12-2010 934831405@GENIA Treebank@formal@@1@S@In the current study, we demonstrate that GC-insensitive asthma is associated with a significantly higher number of GCR-beta-immunoreactive cells in peripheral blood than GC-sensitive asthmatics or normal controls.@@@@1@30@@oe@16-12-2010 934831406@GENIA Treebank@formal@@1@S@Furthermore, we show that patients with GC-insensitive asthma have cytokine-induced abnormalities in the DNA binding capability of the GCR.@@@@1@21@@oe@16-12-2010 934831407@GENIA Treebank@formal@@1@S@These abnormalities can be reproduced by transfection of cell lines with the GCR-beta gene resulting in significant reduction of their GCR-alpha DNA binding capacity.@@@@1@25@@oe@16-12-2010 934831408@GENIA Treebank@formal@@1@S@We conclude that increased expression of GCR-beta is cytokine inducible and may account for GC insensitivity in this common inflammatory condition.@@@@1@22@@oe@16-12-2010 934831801@GENIA Treebank@formal@@1@S@Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3.@@@@1@21@@oe@16-12-2010 934831802@GENIA Treebank@formal@@1@S@Bipotential T/natural killer (NK) progenitor cells are present in the human thymus.@@@@1@15@@oe@16-12-2010 934831803@GENIA Treebank@formal@@1@S@Despite their bipotential capacity, these progenitors develop predominantly to T cells in the thymus.@@@@1@16@@oe@16-12-2010 934831804@GENIA Treebank@formal@@1@S@The mechanisms controlling this developmental choice are unknown.@@@@1@9@@oe@16-12-2010 934831805@GENIA Treebank@formal@@1@S@Here we present evidence that a member(s) of the family of basic helix loop helix (bHLH) transcription factors determines lineage specification of NK/T cell progenitors.@@@@1@31@@oe@16-12-2010 934831806@GENIA Treebank@formal@@1@S@The natural dominant negative HLH factor Id3, which blocks transcriptional activity of a number of known bHLH factors, was expressed in CD34+ progenitor cells by retrovirus-mediated gene transfer.@@@@1@31@@oe@16-12-2010 934831807@GENIA Treebank@formal@@1@S@Constitutive expression of Id3 completely blocks development of CD34+ cells into T cells in a fetal thymic organ culture (FTOC).@@@@1@23@@oe@16-12-2010 934831808@GENIA Treebank@formal@@1@S@In contrast, development into NK cells in an FTOC is enhanced.@@@@1@13@@oe@16-12-2010 934831809@GENIA Treebank@formal@@1@S@Thus, the activity of a bHLH transcription factor is necessary for T lineage differentiation of bipotential precursors, in the absence of which a default pathway leading to NK cell development is chosen.@@@@1@35@@oe@16-12-2010 934831810@GENIA Treebank@formal@@1@S@Our results identify a molecular switch for lineage specification in early lymphoid precursors of humans.@@@@1@16@@oe@16-12-2010 935043401@GENIA Treebank@formal@@1@S@Involvement of different transduction pathways in NF-kappa B activation by several inducers.@@@@1@13@@oe@16-12-2010 935043402@GENIA Treebank@formal@@1@S@Double-stimulation was used to demonstrate that, in a T lymphocytic cell line (CEM), phorbol myristate acetate (PMA) rapidly induced NF-kappa B through a signaling pathway which did not involve reactive oxygen species (ROS) and was different from the activation triggered by either H2O2 or tumor necrosis factor-alpha (TNF-alpha).@@@@1@59@@oe@16-12-2010 935043403@GENIA Treebank@formal@@1@S@Since these latter compounds were known to activate NF-kappa B translocation in a redox-sensitive way, we have demonstrated that NF-kappa B activation by PMA was resistant to antioxidant N-acetyl-L-cysteine (NAC) and sensitive to kinase inhibitors staurosporine and H7 while activation by H2O2 or TNF-alpha were not.@@@@1@50@@oe@16-12-2010 935135201@GENIA Treebank@formal@@1@S@Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein.@@@@1@11@@oe@16-12-2010 935135202@GENIA Treebank@formal@@1@S@Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-kappa B in human atherosclerotic lesions.@@@@1@31@@oe@16-12-2010 935135203@GENIA Treebank@formal@@1@S@The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-kappa B system in human THP-1 monocytic cells as well as adherent monocytes.@@@@1@33@@oe@16-12-2010 935135204@GENIA Treebank@formal@@1@S@Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-kappa B dimers and induced the expression of the target gene IL-8.@@@@1@27@@oe@16-12-2010 935135205@GENIA Treebank@formal@@1@S@This activation of NF-kappa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI.@@@@1@21@@oe@16-12-2010 935135206@GENIA Treebank@formal@@1@S@The oxLDL-induced NF-kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this inhibitor protein.@@@@1@29@@oe@16-12-2010 935135207@GENIA Treebank@formal@@1@S@In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of I kappa B-alpha, accompanied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes.@@@@1@37@@oe@16-12-2010 935135208@GENIA Treebank@formal@@1@S@These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-kappa B/Rel is likely to play an important role in atherogenesis.@@@@1@34@@oe@16-12-2010 935182901@GENIA Treebank@formal@@1@S@Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade.@@@@1@15@@oe@16-12-2010 935182902@GENIA Treebank@formal@@1@S@The Epstein-Barr virus latent membrane protein-1 (LMP-1) is an integral membrane protein which transforms fibroblasts and is essential for EBV-mediated B-cell immortalization.@@@@1@25@@oe@16-12-2010 935182903@GENIA Treebank@formal@@1@S@LMP-1 has been shown to trigger cellular NF-kappa B activity which, however, cannot fully explain the oncogenic potential of LMP-1.@@@@1@24@@oe@16-12-2010 935182904@GENIA Treebank@formal@@1@S@Here we show that LMP-1 induces the activity of the AP-1 transcription factor, a dimer of Jun/Jun or Jun/Fos proteins.@@@@1@22@@oe@16-12-2010 935182905@GENIA Treebank@formal@@1@S@LMP-1 effects on AP-1 are mediated through activation of the c-Jun N-terminal kinase (JNK) cascade, but not the extracellular signal-regulated kinase (Erk) pathway.@@@@1@29@@oe@16-12-2010 935182906@GENIA Treebank@formal@@1@S@Consequently, LMP-1 triggers the activity of the c-Jun N-terminal transactivation domain which is known to be activated upon JNK-mediated phosphorylation.@@@@1@22@@oe@16-12-2010 935182907@GENIA Treebank@formal@@1@S@Deletion analysis indicates that the 55 C-terminal amino acids of the LMP-1 molecule, but not its TRAF interaction domain, are essential for AP-1 activation.@@@@1@27@@oe@16-12-2010 935182908@GENIA Treebank@formal@@1@S@JNK-mediated transcriptional activation of AP-1 is the direct output of LMP-1-triggered signaling, as shown by an inducible LMP-1 mutant.@@@@1@21@@oe@16-12-2010 935182909@GENIA Treebank@formal@@1@S@Using a tetracycline-regulated LMP-1 allele, we demonstrate that JNK is also an effector of non-cytotoxic LMP-1 signaling in B cells, the physiological target cells of EBV.@@@@1@29@@oe@16-12-2010 935182910@GENIA Treebank@formal@@1@S@In summary, our data reveal a novel effector of LMP-1, the SEK/JNK/c-Jun/AP-1 pathway, which contributes to our understanding of the immortalizing and transforming potential of LMP-1.@@@@1@30@@oe@16-12-2010 935236001@GENIA Treebank@formal@@1@S@Suppression of MHC class II expression by human class II trans-activator constructs lacking the N-terminal domain.@@@@1@17@@oe@16-12-2010 935236002@GENIA Treebank@formal@@1@S@The class II trans-activator (CIITA) is a bi- or multi-functional domain protein which plays a critical role in the expression of MHC class II genes.@@@@1@28@@oe@16-12-2010 935236003@GENIA Treebank@formal@@1@S@We report that removal of the N-terminal 151 amino acids, encompassing all of the acidic domain but leaving intact the proline/serine/threonine-rich domain, results in a mutant protein with potent suppressive properties for MHC class II expression.@@@@1@39@@oe@16-12-2010 935236004@GENIA Treebank@formal@@1@S@HeLa cells stably or transiently transfected with mutant CIITA constructs showed up to 99% suppression of MHC class II antigen induction by IFN-gamma and marked suppression of HLA-DRA mRNA expression.@@@@1@32@@oe@16-12-2010 935236005@GENIA Treebank@formal@@1@S@Transient transfection of a B lymphoma line resulted in up to 89% reduction of constitutive MHC class II expression within 5 days and suppression of HLA-DRA mRNA synthesis.@@@@1@30@@oe@16-12-2010 935325101@GENIA Treebank@formal@@1@S@CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival.@@@@1@19@@oe@16-12-2010 935325102@GENIA Treebank@formal@@1@S@CD30 is a cell-surface receptor that can augment lymphocyte activation and survival through its ability to induce the transcription factor NF-kappaB.@@@@1@22@@oe@16-12-2010 935325103@GENIA Treebank@formal@@1@S@CD30, however, has also been implicated in the induction of apoptotic cell death of lymphocytes.@@@@1@18@@oe@16-12-2010 935325104@GENIA Treebank@formal@@1@S@Here we show that one of the effects of CD30 signal transduction is to render cells sensitive to apoptosis induced by the type 1 tumor necrosis factor receptor (TNFR1).@@@@1@32@@oe@16-12-2010 935325105@GENIA Treebank@formal@@1@S@This sensitization is dependent on the TRAF-binding sites within the CD30 cytoplasmic domain.@@@@1@14@@oe@16-12-2010 935325106@GENIA Treebank@formal@@1@S@One of the proteins that binds to these sites is TRAF2, a signal transduction molecule that is also utilized by TNFR1 to mediate the activation of several downstream kinases and transcription factors.@@@@1@34@@oe@16-12-2010 935325107@GENIA Treebank@formal@@1@S@During CD30 signal transduction, we found that binding of TRAF2 to the cytoplasmic domain of CD30 results in the rapid depletion of TRAF2 and the associated protein TRAF1 by proteolysis.@@@@1@32@@oe@16-12-2010 935325108@GENIA Treebank@formal@@1@S@These data suggest a model in which CD30 limits its own ability to transduce cell survival signals through signal-coupled depletion of TRAF2.@@@@1@23@@oe@16-12-2010 935325109@GENIA Treebank@formal@@1@S@Depletion of intracellular TRAF2 and its coassociated proteins also increased the sensitivity of the cell to undergoing apoptosis during activation of death-inducing receptors such as TNFR1.@@@@1@27@@oe@16-12-2010 935325110@GENIA Treebank@formal@@1@S@Consistent with this hypothesis, expression of a dominant-negative form of TRAF2 was found to potentiate TNFR1-mediated death.@@@@1@19@@oe@16-12-2010 935325111@GENIA Treebank@formal@@1@S@These studies provide a potential mechanism through which CD30, as well as other TRAF-binding members of the TNFR superfamily, can negatively regulate cell survival.@@@@1@27@@oe@16-12-2010 935459001@GENIA Treebank@formal@@1@S@Inhibition of proliferation and apoptosis of human and rat T lymphocytes by curcumin, a curry pigment.@@@@1@18@@oe@16-12-2010 935459002@GENIA Treebank@formal@@1@S@Curcumin (diferuoylmethane), the yellow pigment in the rhizome of tumeric (Curcuma longa), an ingredient of curry spice, is known to exhibit a variety of pharmacological effects including antitumor, antiinflammatory, and antiinfectious activities.@@@@1@42@@oe@16-12-2010 935459003@GENIA Treebank@formal@@1@S@Although its precise mode of action remains elusive, curcumin has been shown to suppress the activity of the AP-1 transcription factor in cells stimulated to proliferate.@@@@1@28@@oe@16-12-2010 935459004@GENIA Treebank@formal@@1@S@In this study, we observed that curcumin (50 microM) inhibited proliferation of rat thymocytes stimulated with concanavalin A (Con A) as well as that of human Jurkat lymphoblastoid cells in the logarithmic growth phase.@@@@1@40@@oe@16-12-2010 935459005@GENIA Treebank@formal@@1@S@The pigment also inhibited apoptosis in dexamethasone-treated rat thymocytes and in UV-irradiated Jurkat cells as judged by DNA ladder formation, cellular morphological changes, and flow cytometry analysis.@@@@1@30@@oe@16-12-2010 935459006@GENIA Treebank@formal@@1@S@The inhibition of apoptosis by curcumin in rat thymocytes was accompanied by partial suppression of AP-1 activity.@@@@1@18@@oe@16-12-2010 935459007@GENIA Treebank@formal@@1@S@Complete suppression of AP-1 activity was observed in Con A-treated, proliferating thymocytes.@@@@1@14@@oe@16-12-2010 935459008@GENIA Treebank@formal@@1@S@The capacity of curcumin to inhibit both cell growth and death strongly implies that these two biological processes share a common pathway at some point and that curcumin affects a common step, presumably involving a modulation of the AP-1 transcription factor.@@@@1@43@@oe@16-12-2010 935466701@GENIA Treebank@formal@@1@S@PU.1/Pip and basic helix loop helix zipper transcription factors interact with binding sites in the CD20 promoter to help confer lineage- and stage-specific expression of CD20 in B lymphocytes.@@@@1@30@@oe@16-12-2010 935466702@GENIA Treebank@formal@@1@S@CD20 is a B-lineage-specific gene expressed at the pre-B-cell stage of B-cell development that disappears on differentiation to plasma cells.@@@@1@21@@oe@16-12-2010 935466703@GENIA Treebank@formal@@1@S@As such, it serves as an excellent paradigm for the study of lineage and developmental stage-specific gene expression.@@@@1@20@@oe@16-12-2010 935466704@GENIA Treebank@formal@@1@S@Using in vivo footprinting we identified two sites in the promoter at -45 and -160 that were occupied only in CD20+ B cells.@@@@1@24@@oe@16-12-2010 935466705@GENIA Treebank@formal@@1@S@The -45 site is an E box that binds basic helix-loop-helix-zipper proteins whereas the -160 site is a composite PU.1 and Pip binding site.@@@@1@25@@oe@16-12-2010 935466706@GENIA Treebank@formal@@1@S@Transfection studies with reporter constructs and various expression vectors verified the importance of these sites.@@@@1@16@@oe@16-12-2010 935466707@GENIA Treebank@formal@@1@S@The composite PU.1 and Pip site likely accounts for both lineage and stage-specific expression of CD20 whereas the CD20 E box binding proteins enhance overall promoter activity and may link the promoter to a distant enhancer.@@@@1@37@@oe@16-12-2010 935614401@GENIA Treebank@formal@@1@S@Analysis of interactions between huGATA-3 transcription factor and three GATA regulatory elements of HIV-1 long terminal repeat, by surface plasmon resonance.@@@@1@23@@oe@16-12-2010 935614402@GENIA Treebank@formal@@1@S@Relative affinities of transcriptional regulatory elements for their respective factor have been essentially studied by bandshift analysis.@@@@1@18@@oe@16-12-2010 935614403@GENIA Treebank@formal@@1@S@Here we report a real-time study of factor/DNA interactions using a surface plasmon resonance approach and further characterization of recovered proteins involved in this interaction.@@@@1@26@@oe@16-12-2010 935614404@GENIA Treebank@formal@@1@S@For this purpose, human GATA-3, either recombinant or in nuclear extracts, and three natural GATA elements of the HIV-1 long terminal repeat (sites 1, 2, and 3) were chosen, in which only site 2 is a noncanonical GATA site.@@@@1@48@@oe@16-12-2010 935614405@GENIA Treebank@formal@@1@S@Direct analysis of sensorgrams, with recombinant huGATA-3, allowed the comparison of association and dissociation profiles of the three DNA regions and their ranking according to their relative affinities.@@@@1@31@@oe@16-12-2010 935614406@GENIA Treebank@formal@@1@S@This result, confirmed by competitions with each GATA site, demonstrated the higher relative affinity (at least sevenfold) of site 3.@@@@1@25@@oe@16-12-2010 935614407@GENIA Treebank@formal@@1@S@Interactions between the canonical and unique GATA site 3 and nuclear extracts were also studied in real time and provided information on its association and dissociation rates for native huGATA-3.@@@@1@31@@oe@16-12-2010 935614408@GENIA Treebank@formal@@1@S@Finally, recovered protein was identified as genuine huGATA-3 by SDS-PAGE, Western blotting, and bandshift assays.@@@@1@19@@oe@16-12-2010 935614409@GENIA Treebank@formal@@1@S@Copyright 1997 Academic Press.@@@@1@5@@oe@16-12-2010 935635301@GENIA Treebank@formal@@1@S@TNFalpha cooperates with the protein kinase A pathway to synergistically increase HIV-1 LTR transcription via downstream TRE-like cAMP response elements.@@@@1@21@@oe@16-12-2010 935635302@GENIA Treebank@formal@@1@S@Activating protein-1 (AP-1) binding TPA responsive elements (TRE) are located downstream of the transcription initiation site in the U5 region of the HIV-1 long terminal repeat (LTR).@@@@1@34@@oe@16-12-2010 935635303@GENIA Treebank@formal@@1@S@These downstream sequence elements, termed DSE, can bind both AP-1 and CREB/ATF transcription factors.@@@@1@17@@oe@16-12-2010 935635304@GENIA Treebank@formal@@1@S@Recently, we demonstrated that the DSE are also cAMP-responsive elements (CRE), since they mediated activation signals elicited by cholera toxin (Ctx), a potent activator of the cAMP-dependent protein kinase A (PKA) signal transduction pathway.@@@@1@44@@oe@16-12-2010 935635305@GENIA Treebank@formal@@1@S@In the present study, we demonstrate that the HIV-1 DSE can mediate the transcriptional synergy elicited by the combination of Ctx and TNFalpha.@@@@1@25@@oe@16-12-2010 935635306@GENIA Treebank@formal@@1@S@Ctx combined with TNFalpha or IL-1beta to produce a synergistic increase in p24 antigen production in U1 promonocytic cells.@@@@1@20@@oe@16-12-2010 935635307@GENIA Treebank@formal@@1@S@Transfection studies of LTR reporter constructs indicated that mutation of the DSE sites abrogated the LTR-mediated synergy induced by Ctx and TNFalpha, whereas the synergy induced by Ctx and IL-1beta was unaffected, suggesting TNFalpha and IL-1beta cooperate differently with the cAMP/PKA activation pathway to induce HIV-1 expression in U1 cells.@@@@1@53@@oe@16-12-2010 935635308@GENIA Treebank@formal@@1@S@Because the DSE are also TRE sites, we assessed the effect of the agonist combinations on AP-1-dependent transcription.@@@@1@20@@oe@16-12-2010 935635309@GENIA Treebank@formal@@1@S@TNFalpha as well as IL-1beta cooperated with Ctx to produce a synergistic activation of AP-1-mediated transcription.@@@@1@17@@oe@16-12-2010 935635310@GENIA Treebank@formal@@1@S@These data indicate that the TRE-like cAMP-responsive DSE sites within the 5'-untranslated leader can mediate the transcriptional cooperativity between TNFalpha and the cAMP/PKA pathway.@@@@1@25@@oe@16-12-2010 935635311@GENIA Treebank@formal@@1@S@Since the DSE and TRE sites cannot bind CREB/ATF homodimers, we propose a mechanism in which the HIV-1 DSE bind heterodimers composed of both AP-1 and CREB/ATF proteins.@@@@1@31@@oe@16-12-2010 935635312@GENIA Treebank@formal@@1@S@Copyright 1997 Academic Press.@@@@1@5@@oe@16-12-2010 935649401@GENIA Treebank@formal@@1@S@The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappaB.@@@@1@28@@oe@16-12-2010 935649402@GENIA Treebank@formal@@1@S@The Epstein-Barr virus latent membrane protein 1 (LMP1) is essential for the transformation of B lymphocytes into lymphoblastoid cell lines.@@@@1@23@@oe@16-12-2010 935649403@GENIA Treebank@formal@@1@S@Previous data are consistent with a model that LMP1 is a constitutively activated receptor that transduces signals for transformation through its carboxyl-terminal cytoplasmic tail.@@@@1@25@@oe@16-12-2010 935649404@GENIA Treebank@formal@@1@S@One transformation effector site (TES1), located within the membrane proximal 45 residues of the cytoplasmic tail, constitutively engages tumor necrosis factor receptor-associated factors.@@@@1@28@@oe@16-12-2010 935649405@GENIA Treebank@formal@@1@S@Signals from TES1 are sufficient to drive initial proliferation of infected resting B lymphocytes, but most lymphoblastoid cells infected with a virus that does not express the 155 residues beyond TES1 fail to grow as long-term cell lines.@@@@1@40@@oe@16-12-2010 935649406@GENIA Treebank@formal@@1@S@We now find that mutating two tyrosines to an isoleucine at the carboxyl end of the cytoplasmic tail cripples the ability of EBV to cause lymphoblastoid cell outgrowth, thereby marking a second transformation effector site, TES2.@@@@1@39@@oe@16-12-2010 935649407@GENIA Treebank@formal@@1@S@A yeast two-hybrid screen identified TES2 interacting proteins, including the tumor necrosis factor receptor-associated death domain protein (TRADD).@@@@1@22@@oe@16-12-2010 935649408@GENIA Treebank@formal@@1@S@TRADD was the only protein that interacted with wild-type TES2 and not with isoleucine-mutated TES2.@@@@1@16@@oe@16-12-2010 935649409@GENIA Treebank@formal@@1@S@TRADD associated with wild-type LMP1 but not with isoleucine-mutated LMP1 in mammalian cells, and TRADD constitutively associated with LMP1 in EBV-transformed cells.@@@@1@24@@oe@16-12-2010 935649410@GENIA Treebank@formal@@1@S@In transfection assays, TRADD and TES2 synergistically mediated high-level NF-kappaB activation.@@@@1@13@@oe@16-12-2010 935649411@GENIA Treebank@formal@@1@S@These results indicate that LMP1 appropriates TRADD to enable efficient long-term lymphoblastoid cell outgrowth.@@@@1@15@@oe@16-12-2010 935649412@GENIA Treebank@formal@@1@S@High-level NF-kappaB activation also appears to be a critical component of long-term outgrowth.@@@@1@14@@oe@16-12-2010 935713701@GENIA Treebank@formal@@1@S@Switching gears during T-cell maturation: RANTES and late transcription.@@@@1@11@@oe@16-12-2010 935713702@GENIA Treebank@formal@@1@S@Although much is understood about the induction of genes expressed early (within 24 h) after T-cell activation, little is known about the regulation of expression of genes expressed 'late' (three or more days) post-stimulation.@@@@1@42@@oe@16-12-2010 935713703@GENIA Treebank@formal@@1@S@A better understanding of transcriptional regulation at this important stage of T-cell maturation may yield new insights into T-cell development and new immunotherapeutic targets.@@@@1@25@@oe@16-12-2010 936094501@GENIA Treebank@formal@@1@S@Transcription factor NF-kappaB regulates inducible Oct-2 gene expression in precursor B lymphocytes.@@@@1@13@@oe@16-12-2010 936094502@GENIA Treebank@formal@@1@S@The POU transcription factors Oct-1 and Oct-2 regulate the activity of octamer-dependent promoters, including those that direct transcription from rearranged immunoglobulin genes.@@@@1@24@@oe@16-12-2010 936094503@GENIA Treebank@formal@@1@S@Unlike Oct-1, which is constitutively expressed in many cell types, Oct-2 expression is restricted primarily to B lymphocytes and can be induced in precursor B cells by stimulation with bacterial lipopolysaccharide (LPS).@@@@1@37@@oe@16-12-2010 936094504@GENIA Treebank@formal@@1@S@However, the precise factors that mediate this induction mechanism remain unknown.@@@@1@13@@oe@16-12-2010 936094505@GENIA Treebank@formal@@1@S@In the present study, we monitored Oct-2 expression in cells arrested for the activation of NF-kappaB, an LPS-responsive member of the Rel transcription factor family.@@@@1@28@@oe@16-12-2010 936094506@GENIA Treebank@formal@@1@S@Despite stimulation with LPS, disruption of the NF-kappaB signaling pathway in precursor B cells led to the loss of inducible Oct-2 DNA binding activity in vitro and the suppression of Oct-2-directed transcription in vivo.@@@@1@36@@oe@16-12-2010 936094507@GENIA Treebank@formal@@1@S@This biochemical defect correlated with a specific block to Oct-2 gene expression at the level of transcription, whereas the expression of Oct-1 was unaffected.@@@@1@26@@oe@16-12-2010 936094508@GENIA Treebank@formal@@1@S@The finding that Oct-2 is under NF-kappaB control highlights an important cross-talk mechanism involving two distinct transcription factor families that regulate B lymphocyte function.@@@@1@25@@oe@16-12-2010 936102901@GENIA Treebank@formal@@1@S@Paternal expression of WT1 in human fibroblasts and lymphocytes.@@@@1@10@@oe@16-12-2010 936102902@GENIA Treebank@formal@@1@S@The Wilms' tumor suppressor gene ( WT1 ) was previously identified as being imprinted, with frequent maternal expression in human placentae and fetal brains.@@@@1@27@@oe@16-12-2010 936102903@GENIA Treebank@formal@@1@S@We examined the allele-specific expression of WT1 in cultured human fibroblasts from 15 individuals.@@@@1@15@@oe@16-12-2010 936102904@GENIA Treebank@formal@@1@S@Seven of 15 fibroblast lines were heterozygous for polymorphic alleles, and the expression patterns were variable, i.e., equal, unequal or monoallelic paternal expression in three, two and two cases, respectively.@@@@1@37@@oe@16-12-2010 936102905@GENIA Treebank@formal@@1@S@Exclusive paternal expression of WT1 was also shown in non-cultured peripheral lymphocytes from the latter two individuals.@@@@1@18@@oe@16-12-2010 936102906@GENIA Treebank@formal@@1@S@The allele-specific expression profiles of other imprinted genes, IGF2 and H19, on human chromosome 11 were constant and consistent with those in other tissues.@@@@1@27@@oe@16-12-2010 936102907@GENIA Treebank@formal@@1@S@Our unexpected observations of paternal or biallelic expression of WT1 in fibroblasts and lymphocytes, together with the previous findings of maternal or biallelic expression in placentae and brains, suggest that the allele-specific regulatory system of WT1 is unique and may be controlled by a putative tissue- and individual-specific modifier.@@@@1@52@@oe@16-12-2010 936392001@GENIA Treebank@formal@@1@S@The activation of the JAK2/STAT5 pathway is commonly involved in signaling through the human IL-5 receptor.@@@@1@17@@oe@16-12-2010 936392002@GENIA Treebank@formal@@1@S@The JAK (Janus kinase) family of protein tyrosine kinases and the STATs (signal transducers and activators of transcription) have been shown to be activated in response to a number of cytokines and growth factors.@@@@1@39@@oe@16-12-2010 936392003@GENIA Treebank@formal@@1@S@In this study, we evaluated the activation of JAK/STAT pathway upon human interleukin-5 (hIL-5) stimulation of two different hIL-5-responsive cell lines, hIL-5 receptor alpha-subunit (hIL-5R alpha) cDNA-transfected TF-1 (TF-h5R alpha) and butyric-acid-treated YY-1 (YY-Bu), and peripheral eosinophils.@@@@1@49@@oe@16-12-2010 936392004@GENIA Treebank@formal@@1@S@Immunoprecipitation and electrophoretic mobility shift analysis revealed that tyrosine phosphorylation of JAK2 and activation of STAT5 were induced upon stimulation with hIL-5 in all three cell types, while STAT1 activation was only observed in eosinophils.@@@@1@37@@oe@16-12-2010 936392005@GENIA Treebank@formal@@1@S@These results indicate that JAK2/STAT5 activation is a common JAK/STAT pathway for hIL-5-mediated signal in these cells.@@@@1@18@@oe@16-12-2010 936421901@GENIA Treebank@formal@@1@S@Is celiac disease due to molecular mimicry between gliadin peptide-HLA class II molecule-T cell interactions and those of some unidentified superantigen?@@@@1@22@@oe@16-12-2010 936421902@GENIA Treebank@formal@@1@S@This paper presents a new hypothesis for the etiology and pathogenesis of celiac disease (CD).@@@@1@18@@oe@16-12-2010 936421903@GENIA Treebank@formal@@1@S@It is our contention that CD is triggered by the binding of one or more gliadin peptides to CD-associated HLA class II molecules.@@@@1@24@@oe@16-12-2010 936421904@GENIA Treebank@formal@@1@S@Furthermore, we propose that these putative CD peptides bind to oligosaccharide residues on HLA class II molecules distal to the peptide-binding groove invoking recognition and binding by specialized subsets of gamma delta T cell receptor-bearing lymphocytes.@@@@1@38@@oe@16-12-2010 936421905@GENIA Treebank@formal@@1@S@The binding of these gamma delta T cells serves as a signal for abrogation of oral tolerance to ingested proteins setting in motion a series of immune responses directed against the small intestinal epithelium of CD patients.@@@@1@38@@oe@16-12-2010 936421906@GENIA Treebank@formal@@1@S@CD patients are victimized by this self-distructed immune response because of inheritance of certain combinations of HLA-DQ and DR haplotypes.@@@@1@21@@oe@16-12-2010 936421907@GENIA Treebank@formal@@1@S@Dimers encoded by HLA-DR haplotypes may be the primary restriction elements for lectin-like, gliadin peptides while the degree of immune suppression (or lack thereof) to ingested gliadins is governed by inherited HLA-DQ haplotypes.@@@@1@37@@oe@16-12-2010 936421908@GENIA Treebank@formal@@1@S@Finally, we speculate that molecular mimicry between one or more gliadin peptides and some, as yet unidentified, bacterial or viral superantigen plays a role in disease pathogenesis.@@@@1@31@@oe@16-12-2010 936641501@GENIA Treebank@formal@@1@S@Characterization of CD40 signaling determinants regulating nuclear factor-kappa B activation in B lymphocytes.@@@@1@14@@oe@16-12-2010 936641502@GENIA Treebank@formal@@1@S@CD40 signaling to B cells is important for generating an effective humoral immune response.@@@@1@15@@oe@16-12-2010 936641503@GENIA Treebank@formal@@1@S@CD40 ligation leads to B cell activation events such as proliferation, Ig secretion, isotype switching, and up-regulation of cell surface molecules, as well as the generation of memory B cells.@@@@1@35@@oe@16-12-2010 936641504@GENIA Treebank@formal@@1@S@Many of these events are dependent upon the ability of CD40 to activate the transcription factor NF-kappa B (NF-kappa B).@@@@1@23@@oe@16-12-2010 936641505@GENIA Treebank@formal@@1@S@To define the CD40 signaling components upstream of NF-kappa B activation and the functional consequences downstream of NF-kappa B activation, we examined mouse B cell transfectants expressing wild-type or mutant human CD40.@@@@1@34@@oe@16-12-2010 936641506@GENIA Treebank@formal@@1@S@Analysis of CD40 cytoplasmic domain truncation and point mutants defined a 10-amino acid CD40 cytoplasmic signaling determinant required for NF-kappa B activation.@@@@1@23@@oe@16-12-2010 936641507@GENIA Treebank@formal@@1@S@A threonine residue at position 234, previously shown to be important for CD40 association with TNF receptor-associated factor 2 (TRAF2), TRAF3, and TRAF5, was not required for NF-kappa B activation.@@@@1@37@@oe@16-12-2010 936641508@GENIA Treebank@formal@@1@S@This suggests that in B cells, CD40-induced NF-kappa B activation can occur independently of TRAF2 and TRAF5 association.@@@@1@20@@oe@16-12-2010 936641509@GENIA Treebank@formal@@1@S@NF-kappa B activation was independent of the transmembrane domain of CD40, suggesting that it is independent of p23, a molecule that associates with CD40 in a region other than the cytoplasmic domain.@@@@1@35@@oe@16-12-2010 936641510@GENIA Treebank@formal@@1@S@Proteasome-dependent inhibitory kappa B alpha (I kappa B alpha) and I kappa B beta degradation occurred downstream of CD40 ligation and preceded CD40-mediated NF-kappa B nuclear translocation.@@@@1@30@@oe@16-12-2010 936641511@GENIA Treebank@formal@@1@S@CD40- or pervanadate-mediated I kappa B tyrosine phosphorylation was not detected.@@@@1@12@@oe@16-12-2010 936641512@GENIA Treebank@formal@@1@S@NF-kappa B activation correlated with the ability of CD40 to induce Ab secretion and the up-regulation of ICAM-1 and LFA-1.@@@@1@21@@oe@16-12-2010 936641513@GENIA Treebank@formal@@1@S@However, NF-kappa B activation was insufficient for CD40-mediated up-regulation of B7-1, Fas, and CD23.@@@@1@18@@oe@16-12-2010 936652801@GENIA Treebank@formal@@1@S@Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours.@@@@1@25@@oe@16-12-2010 936652802@GENIA Treebank@formal@@1@S@Intragenic deletions of TSG101, the human homolog of a mouse gene (tsg101) that acts to suppress malignant cell growth, were reported in human breast tumours.@@@@1@30@@oe@16-12-2010 936652803@GENIA Treebank@formal@@1@S@We screened TSG101 for somatic mutations in DNA and RNA samples isolated from a variety of common human malignancies, EBV-immortalised B-cells, and normal lung parenchyma.@@@@1@28@@oe@16-12-2010 936652804@GENIA Treebank@formal@@1@S@Intragenic TSG101 deletions in RNA transcripts were frequently found in all types of samples.@@@@1@15@@oe@16-12-2010 936652805@GENIA Treebank@formal@@1@S@Analysis of DNA failed to show genomic rearrangements corresponding to transcripts containing deletions in the same samples.@@@@1@18@@oe@16-12-2010 936652806@GENIA Treebank@formal@@1@S@The breakpoints of most transcript deletions coincide with genuine or cryptic splice site sequences, suggesting that they result from alternative or aberrant splicing.@@@@1@25@@oe@16-12-2010 936652807@GENIA Treebank@formal@@1@S@A similar spectrum of transcript deletions has previously been described in the putative tumour suppressor gene FHIT.@@@@1@18@@oe@16-12-2010 936652808@GENIA Treebank@formal@@1@S@We analysed FHIT in the same series of RNA samples and detected truncated FHIT transcripts frequently in both tumour and normal tissues.@@@@1@23@@oe@16-12-2010 936652809@GENIA Treebank@formal@@1@S@In addition, transcripts from TSG101, FHIT and seven other genes were analysed in RNA isolated from normal peripheral blood lymphocytes.@@@@1@23@@oe@16-12-2010 936652810@GENIA Treebank@formal@@1@S@Large TSG101 and FHIT intragenic transcript deletions were detected and these appeared to be the predominant transcript in 'aged' lymphocytes.@@@@1@23@@oe@16-12-2010 936652811@GENIA Treebank@formal@@1@S@Similar alterations were not detected in transcripts of the other genes which were analysed.@@@@1@15@@oe@16-12-2010 936652812@GENIA Treebank@formal@@1@S@Our findings demonstrate that truncated TSG101 and FHIT transcripts are commonly detected in both normal and malignant tissues and that a significant fraction of these are likely to be the result of aberrant splicing.@@@@1@35@@oe@16-12-2010 936652813@GENIA Treebank@formal@@1@S@While we cannot exclude that alterations in TSG101 and FHIT occur during cancer development, our data indicate that in this context the commonly observed transcript abnormalities are misleading.@@@@1@31@@oe@16-12-2010 936928701@GENIA Treebank@formal@@1@S@Impaired cortisol binding to glucocorticoid receptors in hypertensive patients.@@@@1@10@@oe@16-12-2010 936928702@GENIA Treebank@formal@@1@S@We compared glucocorticoid receptor binding characteristics and glucocorticoid responsiveness of human mononuclear leukocytes (HML) from hypertensive patients and matched normotensive volunteers.@@@@1@24@@oe@16-12-2010 936928703@GENIA Treebank@formal@@1@S@We also considered associations of these variables with plasma renin activity, aldosterone, cortisol, corticotropin, and electrolyte concentrations.@@@@1@22@@oe@16-12-2010 936928704@GENIA Treebank@formal@@1@S@We calculated binding affinity (Kd; nmol/L) and capacity (Bmax; sites/cell) for dexamethasone and cortisol from homologous and heterologous competition curves for specific [3H]dexamethasone binding sites on HML isolated from the blood of normotensive volunteers and subjects with essential hypertension.@@@@1@46@@oe@16-12-2010 936928705@GENIA Treebank@formal@@1@S@Glucocorticoid responsiveness of HML was evaluated as IC50 values (nmol/L) for dexamethasone and cortisol for the inhibition of lysozyme release.@@@@1@23@@oe@16-12-2010 936928706@GENIA Treebank@formal@@1@S@We measured plasma hormones by radioimmunoassay.@@@@1@7@@oe@16-12-2010 936928707@GENIA Treebank@formal@@1@S@Kd values (mean+/-SE) for cortisol in HML of hypertensive patients were higher than in control subjects (24.6+/-2.4 versus 17.5+/-1.7 nmol/L, P<.04).@@@@1@29@@oe@16-12-2010 936928708@GENIA Treebank@formal@@1@S@Binding capacity (4978+/-391 versus 4131+/-321 sites/cell), Kd values for dexamethasone (6.7+/-0.5 versus 5.7+/-0.3 nmol/L), and IC50 values for dexamethasone (3.4+/-0.3 versus 3.1+/-0.2 nmol/L) and cortisol (12.2+/-1.6 versus 9.5+/-0.3 nmol/L) were not significantly different.@@@@1@44@@oe@16-12-2010 936928709@GENIA Treebank@formal@@1@S@Patients with renin values less than 0.13 ng angiotensin I/L per second were markedly less sensitive to cortisol than those with higher values.@@@@1@24@@oe@16-12-2010 936928710@GENIA Treebank@formal@@1@S@Both Kd (30.3+/-2.5 versus 19.2+/-2.4 nmol/L) and IC50 values (15.5+/-1.8 versus 8.9+/-1.2 nmol/L) for cortisol were significantly higher in patients with lower renin values (P<.03).@@@@1@34@@oe@16-12-2010 936928711@GENIA Treebank@formal@@1@S@Other variables, including plasma hormone and electrolyte values and binding characteristics for dexamethasone, were not different.@@@@1@19@@oe@16-12-2010 936928712@GENIA Treebank@formal@@1@S@These data suggest that cortisol binding to glucocorticoid receptor is slightly impaired in patients with essential hypertension.@@@@1@18@@oe@16-12-2010 936928713@GENIA Treebank@formal@@1@S@In vivo, this could lead to inappropriate binding of cortisol to mineralocorticoid receptors.@@@@1@15@@oe@16-12-2010 936928714@GENIA Treebank@formal@@1@S@Hence, decreased sensitivity to cortisol is associated with renin suppression.@@@@1@12@@oe@16-12-2010 936928715@GENIA Treebank@formal@@1@S@This hypothesis is supported by evidence of hypertension and low renin activity, which others have described in patients with primary glucocorticoid resistance due to mutations of the glucocorticoid receptor.@@@@1@31@@oe@16-12-2010 937126001@GENIA Treebank@formal@@1@S@Ras-related GTP-binding proteins and leukocyte signal transduction.@@@@1@8@@oe@16-12-2010 937126002@GENIA Treebank@formal@@1@S@Many aspects of leukocyte function are regulated by both heterotrimeric and Ras-related GTP-binding proteins, but there is little definite information about their roles in the specialized processes utilized by leukocytes for cell killing.@@@@1@35@@oe@16-12-2010 937126003@GENIA Treebank@formal@@1@S@Recent progress in understanding the regulation of the phagocyte NADPH oxidase by the Rac GTP-binding proteins provides a basis for defining the operational characteristics of one such phagocyte system.@@@@1@30@@oe@16-12-2010 937126004@GENIA Treebank@formal@@1@S@It is clear from various studies that the activity of the NADPH oxidase can be modulated through the regulation of the GTP-GDP state of Rac.@@@@1@26@@oe@16-12-2010 937126005@GENIA Treebank@formal@@1@S@Proteins exist in leukocytes able to modify GTP-binding protein function in this manner, and their activity may be regulated by signals generated on phagocyte stimulation.@@@@1@27@@oe@16-12-2010 937126006@GENIA Treebank@formal@@1@S@Proteins of the Ras superfamily are likely to be involved in a variety of normal phagocyte functions through their ability to modulate the assembly of actin filaments, direct vesicle trafficking and fusion, and so forth.@@@@1@38@@oe@16-12-2010 937159701@GENIA Treebank@formal@@1@S@Repression of human immunodeficiency virus type 1 through the novel cooperation of human factors YY1 and LSF [published erratum appears in J Virol 1998 Feb;72(2):1709]@@@@1@34@@oe@16-12-2010 937159702@GENIA Treebank@formal@@1@S@A subpopulation of stably infected CD4+ cells capable of producing virus upon stimulation has been identified in human immunodeficiency virus (HIV)-positive individuals (T.-W.Chun, D.Finzi, J.Margolick, K.Chadwick, D.Schwartz, and R.F.Siliciano, Nat.Med.1:1284-1290, 1995).@@@@1@46@@oe@16-12-2010 937159703@GENIA Treebank@formal@@1@S@Few host factors that directly limit HIV-1 transcription and could support this state of nonproductive HIV-1 infection have been described.@@@@1@21@@oe@16-12-2010 937159704@GENIA Treebank@formal@@1@S@YY1, a widely distributed human transcription factor, is known to inhibit HIV-1 long terminal repeat (LTR) transcription and virus production.@@@@1@25@@oe@16-12-2010 937159705@GENIA Treebank@formal@@1@S@LSF (also known as LBP-1, UBP, and CP-2) has been shown to repress LTR transcription in vitro, but transient expression of LSF has no effect on LTR activity in vivo.@@@@1@36@@oe@16-12-2010 937159706@GENIA Treebank@formal@@1@S@We report that both YY1 and LSF participate in the formation of a complex that recognizes the initiation region of the HIV-1 LTR.@@@@1@24@@oe@16-12-2010 937159707@GENIA Treebank@formal@@1@S@Further, we have found that these factors cooperate in the repression of LTR expression and viral replication.@@@@1@19@@oe@16-12-2010 937159708@GENIA Treebank@formal@@1@S@This cooperative function may account for the divergent effects of LSF previously observed in vitro and in vivo.@@@@1@19@@oe@16-12-2010 937159709@GENIA Treebank@formal@@1@S@Thus, the cooperation of two general cellular transcription factors may allow for the selective downregulation of HIV transcription.@@@@1@20@@oe@16-12-2010 937159710@GENIA Treebank@formal@@1@S@Through this mechanism of gene regulation, YY1 and LSF could contribute to the establishment and maintenance of a population of cells stably but nonproductively infected with HIV-1.@@@@1@29@@oe@16-12-2010 937244701@GENIA Treebank@formal@@1@S@Extinction of immunoglobulin gene expression in B cells upon fusion with HeLa cells is preceded by rapid nuclear depletion of essential transcription factors and is accompanied by widespread inactivation of genes expressed in a B cell-specific manner.@@@@1@38@@oe@16-12-2010 937244702@GENIA Treebank@formal@@1@S@When immunoglobulin (Ig) expressing B cells are fused with non-B cells, Ig expression is rapidly suppressed at the level of transcription, a phenomenon termed extinction.@@@@1@30@@oe@16-12-2010 937244703@GENIA Treebank@formal@@1@S@Here we demonstrate that fusion of HeLa cells with either diploid or tetraploid B cells (Daudi) results in widespread extinction of several other B cell-encoded genes that are expressed in a B cell-specific manner.@@@@1@37@@oe@16-12-2010 937244704@GENIA Treebank@formal@@1@S@In contrast, expression of B cell-expressed genes that are not dependent on cell-specific controls is unaffected.@@@@1@18@@oe@16-12-2010 937244705@GENIA Treebank@formal@@1@S@We show that the molecular mechanism(s) underlying Ig gene extinction can be explained, at least in part, by a lack of transcription factors that are essential for Ig gene transcription.@@@@1@36@@oe@16-12-2010 937244706@GENIA Treebank@formal@@1@S@These transcription factors are either not produced due to block of transcription of their respective genes (Oct-2, OBF-1, PU.1), or are rendered inactive posttranslationally (NF-kappa B, E47).@@@@1@36@@oe@16-12-2010 937244707@GENIA Treebank@formal@@1@S@By isolating Daudi x HeLa heterokaryons a few hours after fusion, we have studied the initial fate of two B cell-specific transcription factors involved in Ig gene transcription, Oct-2 and NF-kappa B.@@@@1@35@@oe@16-12-2010 937244708@GENIA Treebank@formal@@1@S@This report provides the first demonstration that upon fusion with HeLa cells, the nuclear contents of B cell-expressed transcription factors are depleted within a few hours with kinetics that are as fast or faster than that of Ig gene extinction.@@@@1@42@@oe@16-12-2010 937244709@GENIA Treebank@formal@@1@S@Thus, the extinguishing mechanism is effective very early after fusion.@@@@1@12@@oe@16-12-2010 937244710@GENIA Treebank@formal@@1@S@We suggest that extinction of Ig genes is part of a global mechanism that suppresses the differentiation program foreign to the HeLa phenotype.@@@@1@24@@oe@16-12-2010 937291201@GENIA Treebank@formal@@1@S@Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation.@@@@1@10@@oe@16-12-2010 937291202@GENIA Treebank@formal@@1@S@The functions of basic helix-loop-helix (bHLH) transcription factors in activating differentiation-linked gene expression and in inducing G1 cell cycle arrest are negatively regulated by members of the Id family of HLH proteins.@@@@1@35@@oe@16-12-2010 937291203@GENIA Treebank@formal@@1@S@These bHLH antagonists are induced during a mitogenic signalling response, and they function by sequestering their bHLH targets in inactive heterodimers that are unable to bind to specific gene regulatory (E box) sequences.@@@@1@37@@oe@16-12-2010 937291204@GENIA Treebank@formal@@1@S@Recently, cyclin E-Cdk2- and cyclin A-Cdk2-dependent phosphorylation of a single conserved serine residue (Ser5) in Id2 has been shown to occur during late G1-to-S phase transition of the cell cycle, and this neutralizes the function of Id2 in abrogating E-box-dependent bHLH homo- or heterodimer complex formation in vitro (E.Hara, M.Hall, and G.Peters, EMBO J.16:332-342, 1997).@@@@1@68@@oe@16-12-2010 937291205@GENIA Treebank@formal@@1@S@We now show that an analogous cell-cycle-regulated phosphorylation of Id3 alters the specificity of Id3 for abrogating both E-box-dependent bHLH homo- or heterodimer complex formation in vitro and E-box-dependent reporter gene function in vivo.@@@@1@35@@oe@16-12-2010 937291206@GENIA Treebank@formal@@1@S@Furthermore, compared with wild-type Id3, an Id3 Asp5 mutant (mimicking phosphorylation) is unable to promote cell cycle S phase entry in transfected fibroblasts, whereas an Id3 Ala5 mutant (ablating phosphorylation) displays an activity significantly greater than that of wild-type Id3 protein.@@@@1@49@@oe@16-12-2010 937291207@GENIA Treebank@formal@@1@S@Cdk2-dependent phosphorylation therefore provides a switch during late G1-to-S phase that both nullifies an early G1 cell cycle regulatory function of Id3 and modulates its target bHLH specificity.@@@@1@29@@oe@16-12-2010 937291208@GENIA Treebank@formal@@1@S@These data also demonstrate that the ability of Id3 to promote cell cycle S phase entry is not simply a function of its ability to modulate bHLH heterodimer-dependent gene expression and establish a biologically important mechanism through which Cdk2 and Id-bHLH functions are integrated in the coordination of cell proliferation and differentiation.@@@@1@53@@oe@16-12-2010 937296101@GENIA Treebank@formal@@1@S@OCA-B is a functional analog of VP16 but targets a separate surface of the Oct-1 POU domain [published erratum appears in Mol Cell Biol 1998 Apr;18(4):2430]@@@@1@35@@oe@16-12-2010 937296102@GENIA Treebank@formal@@1@S@OCA-B is a B-cell-specific coregulator of the broadly expressed POU domain transcription factor Oct-1.@@@@1@15@@oe@16-12-2010 937296103@GENIA Treebank@formal@@1@S@OCA-B associates with the Oct-1 POU domain, a bipartite DNA-binding structure containing a POU-specific (POU[S]) domain joined by a flexible linker to a POU homeodomain (POU[H]).@@@@1@32@@oe@16-12-2010 937296104@GENIA Treebank@formal@@1@S@Here, we show that OCA-B alters the activity of Oct-1 in two ways.@@@@1@15@@oe@16-12-2010 937296105@GENIA Treebank@formal@@1@S@It provides a transcriptional activation domain which, unlike Oct-1, activates an mRNA-type promoter effectively, and it stabilizes Oct-1 on the Oct-1-responsive octamer sequence ATGCAAAT.@@@@1@28@@oe@16-12-2010 937296106@GENIA Treebank@formal@@1@S@These properties of OCA-B parallel those displayed by the herpes simplex virus Oct-1 coregulator VP16.@@@@1@16@@oe@16-12-2010 937296107@GENIA Treebank@formal@@1@S@OCA-B, however, interacts with a different surface of the DNA-bound Oct-1 POU domain, interacting with both the POU(S) and POU(H) domains and the center of the ATGCAAAT octamer sequence.@@@@1@33@@oe@16-12-2010 937296108@GENIA Treebank@formal@@1@S@The OCA-B and VP16 interactions with the Oct-1 POU domain are sufficiently different to permit OCA-B and VP16 to bind the Oct-1 POU domain simultaneously.@@@@1@26@@oe@16-12-2010 937296109@GENIA Treebank@formal@@1@S@These results emphasize the structural versatility of the Oct-1 POU domain in its interaction with coregulators.@@@@1@17@@oe@16-12-2010 937446701@GENIA Treebank@formal@@1@S@Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway.@@@@1@12@@oe@16-12-2010 937446702@GENIA Treebank@formal@@1@S@The nuclear factor of activated T cells (NFAT) group of transcription factors is retained in the cytoplasm of quiescent cells.@@@@1@23@@oe@16-12-2010 937446703@GENIA Treebank@formal@@1@S@NFAT activation is mediated in part by induced nuclear import.@@@@1@11@@oe@16-12-2010 937446704@GENIA Treebank@formal@@1@S@This process requires calcium-dependent dephosphorylation of NFAT caused by the phosphatase calcineurin.@@@@1@13@@oe@16-12-2010 937446705@GENIA Treebank@formal@@1@S@The c-Jun amino-terminal kinase (JNK) phosphorylates NFAT4 on two sites.@@@@1@13@@oe@16-12-2010 937446706@GENIA Treebank@formal@@1@S@Mutational removal of the JNK phosphorylation sites caused constitutive nuclear localization of NFAT4.@@@@1@14@@oe@16-12-2010 937446707@GENIA Treebank@formal@@1@S@In contrast, JNK activation in calcineurin-stimulated cells caused nuclear exclusion of NFAT4.@@@@1@14@@oe@16-12-2010 937446708@GENIA Treebank@formal@@1@S@These findings show that the nuclear accumulation of NFAT4 promoted by calcineurin is opposed by the JNK signal transduction pathway.@@@@1@21@@oe@16-12-2010 937464201@GENIA Treebank@formal@@1@S@Hypoxia enhances induction of endothelial ICAM-1: role for metabolic acidosis and proteasomes.@@@@1@14@@oe@16-12-2010 937464202@GENIA Treebank@formal@@1@S@Intercellular adhesion molecule 1 (ICAM-1) is an important molecule in promotion of polymorphonuclear neutrophil transendothelial migration during inflammation.@@@@1@21@@oe@16-12-2010 937464203@GENIA Treebank@formal@@1@S@Coincident with many inflammatory diseases is tissue hypoxia.@@@@1@9@@oe@16-12-2010 937464204@GENIA Treebank@formal@@1@S@Thus we hypothesized that combinations of hypoxia and inflammatory stimuli may differentially regulate expression of endothelial ICAM-1.@@@@1@18@@oe@16-12-2010 937464205@GENIA Treebank@formal@@1@S@Human endothelial cells were exposed to hypoxia in the presence or absence of added lipopolysaccharide (LPS) and examined for expression of functional ICAM-1.@@@@1@26@@oe@16-12-2010 937464206@GENIA Treebank@formal@@1@S@Although hypoxia alone did not induce ICAM-1, the combination of LPS and hypoxia enhanced (3 +/- 0.4-fold over normoxia) ICAM-1 expression.@@@@1@25@@oe@16-12-2010 937464207@GENIA Treebank@formal@@1@S@Combinations of hypoxia and LPS significantly increased lymphocyte binding, and such increases were inhibited by addition of anti-ICAM-1 antibodies or antisense oligonucleotides.@@@@1@24@@oe@16-12-2010 937464208@GENIA Treebank@formal@@1@S@Hypoxic endothelia showed a > 10-fold increase in sensitivity to inhibitors of proteasome activation, and combinations of hypoxia and LPS enhanced proteasome-dependent cytoplasmic-to-nuclear localization of the nuclear transcription factor-kappa B p65 (Rel A) subunit.@@@@1@38@@oe@16-12-2010 937464209@GENIA Treebank@formal@@1@S@Such proteasome activation correlated with hypoxia-evoked decreases in both extracellular and intracellular pH.@@@@1@14@@oe@16-12-2010 937464210@GENIA Treebank@formal@@1@S@We conclude from these studies that endothelial hypoxia provides a novel, proteasome-dependent stimulus for ICAM-1 induction.@@@@1@18@@oe@16-12-2010 937657901@GENIA Treebank@formal@@1@S@Modulation of mRNA expression of a novel human myeloid-selective CCAAT/enhancer binding protein gene (C/EBP epsilon).@@@@1@18@@oe@16-12-2010 937657902@GENIA Treebank@formal@@1@S@Human C/EBP epsilon is a newly cloned gene coding for a CCAAT/enhancer binding protein that may be involved in the regulation of myeloid differentiation.@@@@1@25@@oe@16-12-2010 937657903@GENIA Treebank@formal@@1@S@Our studies showed that levels of C/EBP epsilon mRNA were markedly increased in NB4 cells (promyelocytic leukemia line), because they were induced by 9-cis retinoic acid (9-cis RA) to differentiate towards granulocytes.@@@@1@38@@oe@16-12-2010 937657904@GENIA Treebank@formal@@1@S@Accumulation of C/EBP epsilon mRNA occurred as early as 1 hour after exposure of NB4 cells to 9-cis RA (5 x 10(-7) mol/L); and at 48 hours, levels were increased by 5.1-fold.@@@@1@37@@oe@16-12-2010 937657905@GENIA Treebank@formal@@1@S@Dose-response studies showed that 10(-7) to 10(-6) mol/L 9-cis RA (12 hours) resulted in peak levels of C/EBP epsilon mRNA; but even 10(-10) mol/L 9-cis RA increased levels of these transcripts.@@@@1@35@@oe@16-12-2010 937657906@GENIA Treebank@formal@@1@S@NB4 cells pulse-exposed (30 minutes) to all-trans retinoic acid (ATRA), washed, and cultured (3 days) with either dimethylsulfoxide (DMSO) or hexamethylene bisacetamide (HMBA) had a prominent increase in levels of C/EBP epsilon mRNA and an increase in granulocytic differentiation, but exposure to either DMSO or HMBA alone had no effect on base levels of C/EBP epsilon and did not induce differentiation.@@@@1@75@@oe@16-12-2010 937657907@GENIA Treebank@formal@@1@S@Macrophage-differentiation of NB4 reduced levels of C/EBP epsilon mRNA.@@@@1@10@@oe@16-12-2010 937657908@GENIA Treebank@formal@@1@S@Nuclear run-off assays and half-life studies showed that accumulation of C/EBP epsilon mRNA by 9-cis RA was due to enhanced transcription.@@@@1@22@@oe@16-12-2010 937657909@GENIA Treebank@formal@@1@S@Furthermore, this C/EBP epsilon mRNA accumulation did not require synthesis of new protein factors because 9-cis RA induced C/EBP epsilon mRNA accumulation in the absence of new protein synthesis.@@@@1@31@@oe@16-12-2010 937657910@GENIA Treebank@formal@@1@S@ATRA also induced expression of C/EBP epsilon protein in NB4 cells, as shown by Western blotting.@@@@1@18@@oe@16-12-2010 937657911@GENIA Treebank@formal@@1@S@In contrast to the increase of C/EBP epsilon in 9-cis RA-mediated granulocytic differentiation, the DMSO-induced differentiation of HL-60 cells down the granulocytic pathway was associated with an initial reduction of C/EBP epsilon mRNA levels.@@@@1@36@@oe@16-12-2010 937657912@GENIA Treebank@formal@@1@S@In summary, we have discovered that expression of C/EBP epsilon mRNA is markedly enhanced as the NB4 promyelocytes are induced by retinoids to differentiate towards granulocytes.@@@@1@28@@oe@16-12-2010 937657913@GENIA Treebank@formal@@1@S@This induction of C/EBP epsilon mRNA expression is transcriptionally mediated and occurs in the absence of synthesis of additional protein factors.@@@@1@22@@oe@16-12-2010 937657914@GENIA Treebank@formal@@1@S@We suspect that the C/EBP epsilon promoter/enhancer contains a retinoic acid-response element that is directly stimulated by retinoids.@@@@1@19@@oe@16-12-2010 937801301@GENIA Treebank@formal@@1@S@Relationship between glucocorticoid receptor and response to glucocorticoid therapy in ulcerative colitis.@@@@1@13@@oe@16-12-2010 937801302@GENIA Treebank@formal@@1@S@PURPOSE: To clarify the relationship between the glucocorticoid receptor and the effectiveness of glucocorticoid therapy in patients with ulcerative colitis, we investigated the number and apparent dissociation constant of glucocorticoid receptor in peripheral blood mononuclear leukocytes of patients with ulcerative colitis.@@@@1@44@@oe@16-12-2010 937801303@GENIA Treebank@formal@@1@S@MATERIALS AND METHODS: Eleven patients with ulcerative colitis (5 who responded to intravenous glucocorticoids and 6 who did not) and ten control subjects were studied.@@@@1@29@@oe@16-12-2010 937801304@GENIA Treebank@formal@@1@S@The number and apparent dissociation constant of glucocorticoid receptor were measured using a whole-cell binding assay.@@@@1@17@@oe@16-12-2010 937801305@GENIA Treebank@formal@@1@S@Results were expressed as a median (interquartile range).@@@@1@11@@oe@16-12-2010 937801306@GENIA Treebank@formal@@1@S@RESULTS: The number of glucocorticoid receptors from the six nonresponders, five responders, and ten healthy controls were 4922 (range, 4484-5643), 3413 (range, 3183-4450), and 3610 (range, 2594-3979) binding sites/cell, respectively.@@@@1@46@@oe@16-12-2010 937801307@GENIA Treebank@formal@@1@S@The apparent dissociation constant of the glucocorticoid receptors from the nonresponders, responders, and healthy controls were 7.03 (range, 5.66-10), 4.27 (range, 4-5.13), and 6.18 (range, 5.86-6.74) nM, respectively.@@@@1@43@@oe@16-12-2010 937801308@GENIA Treebank@formal@@1@S@Nonresponders had a significant increase both in the number of binding sites and in the apparent dissociation constant compared with responders (P = 0.045; P = 0.029).@@@@1@31@@oe@16-12-2010 937801309@GENIA Treebank@formal@@1@S@CONCLUSIONS: The increased number and apparent dissociation constant of glucocorticoid receptor are closely associated with the effectiveness of glucocorticoid therapy.@@@@1@22@@oe@16-12-2010 937801310@GENIA Treebank@formal@@1@S@The measurement of the number and apparent dissociation constant of glucocorticoid receptor may be useful in predicting response to glucocorticoids.@@@@1@21@@oe@16-12-2010