877357601@GENIA Treebank@formal@@1@S@The role of early growth response gene 1 (egr-1) in regulation of the immune response.@@@@1@18@@oe@16-12-2010 877357602@GENIA Treebank@formal@@1@S@The induction of immediate early genes in cells of the immune system is critical to determining the ultimate outcome of exposure to antigen.@@@@1@24@@oe@16-12-2010 877357603@GENIA Treebank@formal@@1@S@The importance of many of these genes relates to the role their transcription factor products play in dictating patterns of expression of downstream, function-related genes.@@@@1@27@@oe@16-12-2010 877357604@GENIA Treebank@formal@@1@S@Evidence from several systems indicates that the immediate early gene, egr-1 may be of particular importance in the immune system.@@@@1@22@@oe@16-12-2010 877357605@GENIA Treebank@formal@@1@S@Recently, the egr-1 promoter has been shown to be highly responsive to the diverse biochemical signals generated by antigen and cytokines in cells of the immune system.@@@@1@29@@oe@16-12-2010 877357606@GENIA Treebank@formal@@1@S@Furthermore, an important role for egr-1 in determining the differentiation pathway of myeloid cell precursors has been recently elaborated.@@@@1@21@@oe@16-12-2010 877357607@GENIA Treebank@formal@@1@S@Finally, potential targets of regulation by the zinc-finger transcription factor encoded by egr-1 include the interleukin-2, CD44, ICAM-1, and tumor necrosis factor genes.@@@@1@28@@oe@16-12-2010 877357608@GENIA Treebank@formal@@1@S@The role of egr-1 in regulation of the immune response will be discussed in the context of these recent studies.@@@@1@21@@oe@16-12-2010 878015901@GENIA Treebank@formal@@1@S@Absence of T-cell- and B-cell-specific transcription factors TCF-1, GATA-3, and BSAP in Hodgkin's Reed-Sternberg cells.@@@@1@19@@oe@16-12-2010 878015902@GENIA Treebank@formal@@1@S@Based on the presence of T cell receptor-beta (TcR-beta) gene rearrangements in L428 and HDLM-1 cells, the expression of CD2 in HDLM-1 cells, and the presence of immunoglobulin heavy-chain (IgH) gene rearrangement in KM-H2 cells, some researchers have concluded that these long-term cell lines derived from patients with Hodgkin's disease are lymphoid in nature.@@@@1@63@@oe@16-12-2010 878015903@GENIA Treebank@formal@@1@S@The information obtained from these cell lines has also been used in arguments for a lymphoid origin of H-RS cells in tissue despite the frequent absence of lymphoid markers and Ig/TcR gene rearrangements in these cells.@@@@1@37@@oe@16-12-2010 878015904@GENIA Treebank@formal@@1@S@We questioned whether one can use the limited expression of lymphoid markers or the limited gene rearrangement to conclude that H-RS cells have a lymphoid origin, because these markers may be aberrant in tumor cells.@@@@1@37@@oe@16-12-2010 878015905@GENIA Treebank@formal@@1@S@In this study, we examined the expression of two T-cell-specific transcription factors (TCF-1 and GATA-3) and one B-cell-specific transcription factor (BSAP) in cultured H-RS cells by using a gel mobility shift assay.@@@@1@38@@oe@16-12-2010 878015906@GENIA Treebank@formal@@1@S@The sensitivity and specificity of this assay for determination of cell lineage have been established in a large number of cultured human and murine cell lines.@@@@1@27@@oe@16-12-2010 878015907@GENIA Treebank@formal@@1@S@All three types of H-RS cell lines were consistently negative for BSAP, TCF-1, and GATA-3.@@@@1@18@@oe@16-12-2010 878015908@GENIA Treebank@formal@@1@S@The absence of GATA-3 was confirmed in H-RS cells in tissues by an in situ hybridization technique.@@@@1@18@@oe@16-12-2010 878015909@GENIA Treebank@formal@@1@S@Virtually all B-cell lines, with the exception of some myeloma cell lines, are positive for BSAP, which is the transcription factor for promoters for several B-cell markers, including VpreB1, lambda 5, CD19, and CD20.@@@@1@42@@oe@16-12-2010 878015910@GENIA Treebank@formal@@1@S@All T-cell lines tested were positive for TCF-1 and GATA-3, which are the transcription factors for promoters for several T-cell-restricted markers, including CD2, CD3, TcR, and lck.@@@@1@33@@oe@16-12-2010 878015911@GENIA Treebank@formal@@1@S@The absence of BSAP, TCF-1, and GATA-3 clearly indicates an underlying difference between H-RS cells and lymphoid cells.@@@@1@21@@oe@16-12-2010 878074701@GENIA Treebank@formal@@1@S@Translocation (3;14)(q27;q11): a new variant translocation in a patient with non-Hodgkin's lymphoma of B-cell type with BCL6 rearrangement.@@@@1@21@@oe@16-12-2010 878074702@GENIA Treebank@formal@@1@S@We report a 65-year-old woman with non-Hodgkin's lymphoma (NHL) carrying a t(3;14)(q27;q11) and BCL6 rearrangement in the affected cells.@@@@1@23@@oe@16-12-2010 878074703@GENIA Treebank@formal@@1@S@She had generalized lymphadenopathy and the bone marrow was infiltrated by lymphoma cells at presentation.@@@@1@16@@oe@16-12-2010 878074704@GENIA Treebank@formal@@1@S@Histological diagnosis was "malignant lymphoma, diffuse, large cell" type according to an International Working Formulation.@@@@1@20@@oe@16-12-2010 878074705@GENIA Treebank@formal@@1@S@Chromosome analysis revealed a t(3;14)(q27;q11), which is a new variant translocation of t(3;14) (q27;q32).@@@@1@15@@oe@16-12-2010 878074706@GENIA Treebank@formal@@1@S@Southern blot analysis showed rearrangement of BCL6, JH, and TCR beta but not of TCR delta.@@@@1@19@@oe@16-12-2010 878074707@GENIA Treebank@formal@@1@S@Cosmid probe of BCL6 hybridized to 14q11 and 3q27 by fluorescence in situ hybridization (FISH).@@@@1@18@@oe@16-12-2010 878074708@GENIA Treebank@formal@@1@S@Although the band 14q11 is a locus of T-cell receptor alpha- and delta-chains (TCR alpha/delta), lymphoma cells expressed B-cell, IgGk phenotype.@@@@1@26@@oe@16-12-2010 878074709@GENIA Treebank@formal@@1@S@The findings suggest that a novel proto-oncogene in the vicinity of TCR alpha/delta is involved in this translocation.@@@@1@19@@oe@16-12-2010 878632401@GENIA Treebank@formal@@1@S@Differential regulation of IL-6 gene transcription and expression by IL-4 and IL-10 in human monocytic cell lines.@@@@1@18@@oe@16-12-2010 878632402@GENIA Treebank@formal@@1@S@IL-4 and IL-10 inhibit the cytokine production and mRNA expression by monocytes/macrophages.@@@@1@13@@oe@16-12-2010 878632403@GENIA Treebank@formal@@1@S@To investigate the molecular mechanism of the inhibitory effect on transcriptional or post-transcriptional regulation of IL-6 gene expression by IL-4 and IL-10, we studied IL-6 production, expression level of IL-6 mRNA, IL-6 promoter activity, transcriptional activity of NF-kappaB and NF-IL-6, and IL-6 mRNA stability in human monocytic cell lines, THP-1 and U937, stimulated by PMA and LPS in the absence or the presence of IL-4 or IL-10.@@@@1@75@@oe@16-12-2010 878632404@GENIA Treebank@formal@@1@S@Both IL-4 and IL-10 were seen to inhibit IL-6 production and the expression of IL-6 mRNA in both monocytic cell lines studied.@@@@1@23@@oe@16-12-2010 878632405@GENIA Treebank@formal@@1@S@In chloramphenicol acetyltransferase assays, utilizing the transient transfection of a chloramphenicol acetyltransferase reporter plasmid containing the IL-6 gene promoter, IL-4, but not IL-10, suppressed the transcriptional activity of the IL-6 gene promoter stimulated by PMA and LPS.@@@@1@42@@oe@16-12-2010 878632406@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assays showed that IL-4, but not IL-10, inhibited nuclear NF-kappaB activity, and that IL-4 and IL-10 did not affect NF-IL-6 activity.@@@@1@28@@oe@16-12-2010 878632407@GENIA Treebank@formal@@1@S@On the other hand, IL-10 enhanced the degradation of IL-6 mRNA in a mRNA stability assay.@@@@1@18@@oe@16-12-2010 878632408@GENIA Treebank@formal@@1@S@These results suggest that IL-4 may inhibit the transcription of the IL-6 gene by affecting NF-kappaB binding activity, while IL-10 may inhibit the IL-6 mRNA levels post-transcriptionally, without suppressing promoter activity.@@@@1@34@@oe@16-12-2010 878632409@GENIA Treebank@formal@@1@S@Therefore, we conclude that IL-4 and IL-10 inhibit IL-6 production by different mechanisms in human monocytic cell lines.@@@@1@20@@oe@16-12-2010 878795301@GENIA Treebank@formal@@1@S@Quantitation of beta 1 triiodothyronine receptor mRNA in human tissues by competitive reverse transcription polymerase chain reaction.@@@@1@18@@oe@16-12-2010 878795302@GENIA Treebank@formal@@1@S@Thyroid hormones act by binding to nuclear receptor proteins, the thyroid hormone receptors (TR) alpha and beta.@@@@1@21@@oe@16-12-2010 878795303@GENIA Treebank@formal@@1@S@Data from cell culture and animal studies indicate that TR expression may be regulated to modulate target organ responsiveness to thyroid hormone.@@@@1@23@@oe@16-12-2010 878795304@GENIA Treebank@formal@@1@S@To investigate whether such adaptive changes in TR expression occur in humans, we determined the mRNA levels of the hTR beta 1 in various thyroid states.@@@@1@28@@oe@16-12-2010 878795305@GENIA Treebank@formal@@1@S@Patients with overt hypo- or hyperthyroidism were enrolled in the study.@@@@1@12@@oe@16-12-2010 878795306@GENIA Treebank@formal@@1@S@Total RNA was isolated from peripheral blood mononuclear cells and hTR beta 1 mRNA levels determined by quantitative competitive reverse transcription PCR.@@@@1@23@@oe@16-12-2010 878795307@GENIA Treebank@formal@@1@S@For comparison, hTR beta 1 mRNA levels were determined in lymphocytes and normal thyroid tissue of euthyroid patients.@@@@1@20@@oe@16-12-2010 878795308@GENIA Treebank@formal@@1@S@Human TR beta 1 mRNA levels in lymphocytes were 1.8 +/- 0.4, 1.9 +/- 0.5, 1.1 +/- 0.4 10(-18) mol/microgram RNA in hypo-, eu- and hyperthyroid patients, respectively, corresponding to an estimated 0.5 -2 molecules per cell.@@@@1@44@@oe@16-12-2010 878795309@GENIA Treebank@formal@@1@S@Although the mean hTR beta 1 mRNA levels were 40% lower in hyperthyroid than in euthyroid subjects, this difference did not reach statistical significance.@@@@1@27@@oe@16-12-2010 878795310@GENIA Treebank@formal@@1@S@Similar levels of hTR beta 1 mRNA levels were detected in thyroid gland from euthyroid patients.@@@@1@17@@oe@16-12-2010 878795311@GENIA Treebank@formal@@1@S@In summary, we developed an assay for the quantitative determination of hTR beta 1 mRNA levels in small human tissue samples, containing as little as 50 ng of total RNA.@@@@1@33@@oe@16-12-2010 878795312@GENIA Treebank@formal@@1@S@Absolute hTR beta 1 mRNA levels are very low with an estimated one molecule of mRNA being present in a mononuclear blood cell or thyrocyte.@@@@1@26@@oe@16-12-2010 878795313@GENIA Treebank@formal@@1@S@No up-regulation of hTR beta 1 was seen in hypothyroid relative to euthyroid patients.@@@@1@15@@oe@16-12-2010 878795314@GENIA Treebank@formal@@1@S@However, there is a non-significant trend towards a down-regulation of hTR beta 1 mRNA levels in hyperthyroid patients.@@@@1@20@@oe@16-12-2010 879036701@GENIA Treebank@formal@@1@S@Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation.@@@@1@15@@oe@16-12-2010 879036702@GENIA Treebank@formal@@1@S@BCL-2-deficient T cells demonstrate accelerated cell cycle progression and increased apoptosis following activation.@@@@1@14@@oe@16-12-2010 879036703@GENIA Treebank@formal@@1@S@Increasing the levels of BCL-2 retarded the G0-->S transition, sustained the levels of cyclin-dependent kinase inhibitor p27Kip1, and repressed postactivation death.@@@@1@26@@oe@16-12-2010 879036704@GENIA Treebank@formal@@1@S@Proximal signal transduction events and immediate early gene transcription were unaffected.@@@@1@12@@oe@16-12-2010 879036705@GENIA Treebank@formal@@1@S@However, the transcription and synthesis of interleukin 2 and other delayed early cytokines were markedly attenuated by BCL-2.@@@@1@20@@oe@16-12-2010 879036706@GENIA Treebank@formal@@1@S@In contrast, a cysteine protease inhibitor that also blocks apoptosis had no substantial affect upon cytokine production.@@@@1@19@@oe@16-12-2010 879036707@GENIA Treebank@formal@@1@S@InterleUkin 2 expression requires several transcription factors of which nuclear translocation of NFAT (nuclear factor of activated T cells) and NFAT-mediated transactivation were impaired by BCL-2.@@@@1@29@@oe@16-12-2010 879036708@GENIA Treebank@formal@@1@S@Thus, select genetic aberrations in the apoptotic pathway reveal a cell autonomous coregulation of activation.@@@@1@17@@oe@16-12-2010 879037101@GENIA Treebank@formal@@1@S@Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2.@@@@1@12@@oe@16-12-2010 879037102@GENIA Treebank@formal@@1@S@Expression of the human immunodeficiency virus type 1 (HIV) protease in cultured cells leads to apoptosis, preceded by cleavage of bcl-2, a key negative regulator of cell death.@@@@1@33@@oe@16-12-2010 879037103@GENIA Treebank@formal@@1@S@In contrast, a high level of bcl-2 protects cells in vitro and in vivo from the viral protease and prevents cell death following HIV infection of human lymphocytes, while reducing the yields of viral structural proteins, infectivity, and tumor necrosis factor alpha.@@@@1@47@@oe@16-12-2010 879037104@GENIA Treebank@formal@@1@S@We present a model for HIV replication in which the viral protease depletes the infected cells of bcl-2, leading to oxidative stress-dependent activation of NF kappa B, a cellular factor required for HIV transcription, and ultimately to cell death.@@@@1@43@@oe@16-12-2010 879037105@GENIA Treebank@formal@@1@S@Purified bcl-2 is cleaved by HIV protease between phenylalanine 112 and alanine 113.@@@@1@14@@oe@16-12-2010 879037106@GENIA Treebank@formal@@1@S@The results suggest a new option for HIV gene therapy; bcl-2 muteins that have noncleavable alterations surrounding the HIV protease cleavage site.@@@@1@24@@oe@16-12-2010 879037601@GENIA Treebank@formal@@1@S@Activation of Stat 5b in erythroid progenitors correlates with the ability of ErbB to induce sustained cell proliferation.@@@@1@19@@oe@16-12-2010 879037602@GENIA Treebank@formal@@1@S@Self renewal of normal erythroid progenitors is induced by the receptor tyrosine kinase c-ErbB, whereas other receptors (c-Kit/Epo-R) regulate erythroid differentiation.@@@@1@25@@oe@16-12-2010 879037603@GENIA Treebank@formal@@1@S@To address possible mechanisms that could explain this selective activity of c-ErbB, we analyzed the ability of these receptors to activate the different members of the Stat transcription factor family.@@@@1@32@@oe@16-12-2010 879037604@GENIA Treebank@formal@@1@S@Ligand activation of c-ErbB induced the tyrosine phosphorylation, DNA-binding, and reporter gene transcription of Stat 5b in erythroblasts.@@@@1@21@@oe@16-12-2010 879037605@GENIA Treebank@formal@@1@S@In contrast, ligand activation of c-Kit was unable to induce any of these effects in the same cells.@@@@1@20@@oe@16-12-2010 879037606@GENIA Treebank@formal@@1@S@Activation of the erythropoietin receptor caused specific DNA-binding of Stat 5b, but failed to induce reporter gene transcription.@@@@1@20@@oe@16-12-2010 879037607@GENIA Treebank@formal@@1@S@These biochemical findings correlate perfectly with the selective ability of c-ErbB to cause sustained self renewal in erythroid progenitors.@@@@1@20@@oe@16-12-2010 879488801@GENIA Treebank@formal@@1@S@Calcineurin mutants render T lymphocytes resistant to cyclosporin A.@@@@1@10@@oe@16-12-2010 879488802@GENIA Treebank@formal@@1@S@The immunosuppressants cyclosporin A (CsA) and FK506 have been widely used to prevent and treat graft rejection after human organ and tissue transplantations.@@@@1@26@@oe@16-12-2010 879488803@GENIA Treebank@formal@@1@S@CsA and FK506 associate with intracellular binding proteins (i.e., CsA with cyclophilin A and FK506 with FKBP12) to form protein/drug complexes that suppress the immune system by preventing activation of T cells in response to antigen presentation.@@@@1@41@@oe@16-12-2010 879488804@GENIA Treebank@formal@@1@S@The common target of CsA and FK506 is calcineurin, a Ca2+/calmodulin-regulated, serine/threonine-specific protein phosphatase that regulates the nuclear import of a transcription factor, NF-AT, required for expression of T cell activation genes.@@@@1@37@@oe@16-12-2010 879488805@GENIA Treebank@formal@@1@S@In previous studies, we identified calcineurin mutations that block binding by the cyclophilin A/CsA or FKBP12/FK506 complexes and thereby render yeast cells resistant to the antifungal effects of CsA or FK506.@@@@1@33@@oe@16-12-2010 879488806@GENIA Treebank@formal@@1@S@In this report, we demonstrate that the corresponding mutations in murine calcineurin render the T cell receptor signal transduction cascade CsA resistant in human Jurkat T cells.@@@@1@29@@oe@16-12-2010 879488807@GENIA Treebank@formal@@1@S@Our findings support the recently determined calcineurin X-ray crystal structure, provide evidence that calcineurin is the only CsA-sensitive component limiting signaling from the T cell receptor to the nucleus, and suggest a means to render cells and tissues resistant to the toxic side effects of CsA and FK506.@@@@1@51@@oe@16-12-2010 879637201@GENIA Treebank@formal@@1@S@Evidence for lowered induction of nuclear factor kappa B in activated human T lymphocytes during aging.@@@@1@17@@oe@16-12-2010 879637202@GENIA Treebank@formal@@1@S@Transcription factor NF kappa B (nuclear factor kappa B) is induced in T lymphocytes from young individuals following activation with a variety of stimuli including anti-CD3, phorbol myristate acetate (PMA), and tumor necrosis factor-alpha (TNF-alpha).@@@@1@44@@oe@16-12-2010 879637203@GENIA Treebank@formal@@1@S@In contrast, activated T lymphocytes from older individuals show a significant reduction in the induction of NF kappa B in response to the same stimuli.@@@@1@27@@oe@16-12-2010 879637204@GENIA Treebank@formal@@1@S@The age-related decline in induction of NF kappa B could not be attributed to alteration in the composition of subunits, p50 and p65 were found to be the predominant subunits of induced NF kappa B in T cells from young as well as elderly donors.@@@@1@47@@oe@16-12-2010 879637205@GENIA Treebank@formal@@1@S@Furthermore, similar levels of NF kappa B were found in the cytosols of unactivated T cells from both young and elderly donors suggesting that precursor levels of NF kappa B remain unaltered during aging.@@@@1@36@@oe@16-12-2010 879637206@GENIA Treebank@formal@@1@S@These results suggest that an age-associated decline in the induction of NF kappa B in activated T cells from elderly individuals may be attributable to altered regulation of the inhibitor, I kappa B, and may play an important role in immune dysregulation accompanying aging.@@@@1@47@@oe@16-12-2010 879770801@GENIA Treebank@formal@@1@S@Interaction of HTLV-I Tax with the human proteasome: implications for NF-kappa B induction.@@@@1@15@@oe@16-12-2010 879770802@GENIA Treebank@formal@@1@S@The human T-cell leukemia virus type I (HTLV-I) has been etiologically associated with the development of the adult T-cell leukemia (ATL) as well as degenerative neurologic syndrome termed tropical spastic paraparesis (TSP).@@@@1@39@@oe@16-12-2010 879770803@GENIA Treebank@formal@@1@S@HTLV-I encodes a potent transactivator protein termed Tax that appears to play an important role in the process of T-cell immortalization.@@@@1@22@@oe@16-12-2010 879770804@GENIA Treebank@formal@@1@S@Even though the mechanisms by which Tax induces transformation are still unknown, it seems likely that the ability of Tax to alter the expression of many cellular genes plays an important part in this process.@@@@1@37@@oe@16-12-2010 879770805@GENIA Treebank@formal@@1@S@Tax does not bind directly to DNA but rather deregulates the activity of cellular transcription factors.@@@@1@17@@oe@16-12-2010 879770806@GENIA Treebank@formal@@1@S@One family of host transcription factors whose activity is altered by Tax includes NF-kappa B/Rel.@@@@1@16@@oe@16-12-2010 879770807@GENIA Treebank@formal@@1@S@These transcription factors are post-transcriptionally regulated by their assembly with a second family of inhibitory proteins termed I kappa B that serve to sequester the NF-kappa B/Rel complexes in the cytoplasm.@@@@1@32@@oe@16-12-2010 879770808@GENIA Treebank@formal@@1@S@Upon cellular activation, I kappa B alpha is phosphorylated, polyubiquitinated, and degraded in the proteasome.@@@@1@19@@oe@16-12-2010 879770809@GENIA Treebank@formal@@1@S@This proteolytic event liberates NF-kappa B, permitting its rapid translocation into the nucleus where it binds to its cognate enhancer elements.@@@@1@23@@oe@16-12-2010 879770810@GENIA Treebank@formal@@1@S@Similarly, the p105 precursor of the NF-kappa B p50 subunit is also post-translationally processed in the proteasome.@@@@1@19@@oe@16-12-2010 879770811@GENIA Treebank@formal@@1@S@The mechanisms by which Tax activates NF-kappa B remain unclear, and findings presented in the literature are often controversial.@@@@1@21@@oe@16-12-2010 879770812@GENIA Treebank@formal@@1@S@We identified a physical interaction between Tax and the HsN3 subunit of the human proteasome.@@@@1@16@@oe@16-12-2010 879770813@GENIA Treebank@formal@@1@S@This raises the intriguing possibility that physical association of the HsN3 proteasome subunit with HTLV-I Tax coupled with the independent interaction of Tax with either p100 or p65-I kappa B alpha targets these cytoplasmic NF-kappa B/Rel complexes to the proteasome for processing.@@@@1@43@@oe@16-12-2010 879917701@GENIA Treebank@formal@@1@S@Epstein-Barr viral latency is disrupted by the immediate-early BRLF1 protein through a cell-specific mechanism.@@@@1@15@@oe@16-12-2010 879917702@GENIA Treebank@formal@@1@S@Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, is a human herpesvirus associated with epithelial cell malignancies (nasopharyngeal carcinoma) as well as B-cell malignancies.@@@@1@32@@oe@16-12-2010 879917703@GENIA Treebank@formal@@1@S@Understanding how viral latency is disrupted is a central issue in herpesvirus biology.@@@@1@14@@oe@16-12-2010 879917704@GENIA Treebank@formal@@1@S@Epithelial cells are the major site of lytic EBV replication within the human host, and viral reactivation occurs in EBV-associated nasopharyngeal carcinomas.@@@@1@24@@oe@16-12-2010 879917705@GENIA Treebank@formal@@1@S@It is known that expression of a single viral immediate-early protein, BZLF1, is sufficient to initiate the switch from latent to lytic infection in B cells.@@@@1@29@@oe@16-12-2010 879917706@GENIA Treebank@formal@@1@S@Cellular regulation of BZLF1 transcription is therefore thought to play a key role in regulating the stringency of viral latency.@@@@1@21@@oe@16-12-2010 879917707@GENIA Treebank@formal@@1@S@Here we show that, unexpectedly, expression of another viral immediate-early protein, BRLF1, can disrupt viral latency in an epithelial cell-specific fashion.@@@@1@26@@oe@16-12-2010 879917708@GENIA Treebank@formal@@1@S@Therefore, the mechanisms leading to disruption of EBV latency appear to be cell-type specific.@@@@1@16@@oe@16-12-2010 880116301@GENIA Treebank@formal@@1@S@Retinoid differentiation therapy in promyelocytic leukemia.@@@@1@7@@oe@16-12-2010 880116302@GENIA Treebank@formal@@1@S@Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia characterized by the morphology of the blast cells, a specific t(15;17) translocation, and risks of definite coagulopathy.@@@@1@34@@oe@16-12-2010 880116303@GENIA Treebank@formal@@1@S@Recently this leukemia was further characterized by an exquisite sensitivity to all-trans retinoic acid's differentiation effect and the production of a fusion gene altering the gene of RARalpha and a novel gene PML.@@@@1@35@@oe@16-12-2010 880116304@GENIA Treebank@formal@@1@S@In vivo differentiation therapy with retinoids in APL patients follows strict guidelines related both to the APL cell and the biodisposal of all-trans retinoic acid.@@@@1@26@@oe@16-12-2010 880442201@GENIA Treebank@formal@@1@S@IL4 and IL13 receptors share the gamma c chain and activate STAT6, STAT3 and STAT5 proteins in normal human B cells.@@@@1@23@@oe@16-12-2010 880442202@GENIA Treebank@formal@@1@S@IL13 induces the same biological effects as IL4 in normal human B cells.@@@@1@14@@oe@16-12-2010 880442203@GENIA Treebank@formal@@1@S@We show that as in the IL4R complex, both IL4R alpha and IL2R gamma c are components of the IL13R and that both cytokines induced STAT6, STAT3 and STAT5 activation in B cells.@@@@1@36@@oe@16-12-2010 880442204@GENIA Treebank@formal@@1@S@In spite of this similar downstream signalling, IL4 and IL13 used a different set of Janus kinases: IL13 is unable to activate JAK1 and JAK3.@@@@1@28@@oe@16-12-2010 880443701@GENIA Treebank@formal@@1@S@Attenuated function of a variant form of the helix-loop-helix protein, Id-3, generated by an alternative splicing mechanism.@@@@1@20@@oe@16-12-2010 880443702@GENIA Treebank@formal@@1@S@The Id family of helix-loop-helix proteins function as negative regulators of DNA binding, basic helix-loop-helix proteins in the regulation of cell growth and differentiation.@@@@1@26@@oe@16-12-2010 880443703@GENIA Treebank@formal@@1@S@We report here on the identification of a 17 kDa variant of the 14 kDa Id-3 protein termed Id-3L (long version) which possesses a unique 60 amino acid carboxy-terminus generated by read through of a 'coding intron' and alternative splicing.@@@@1@45@@oe@16-12-2010 880443704@GENIA Treebank@formal@@1@S@Northern analysis revealed expression of a minor 1.1 kb Id-3L transcript together with the predominant 0.95 kb Id-3 transcript in the majority of adult human tissues analysed.@@@@1@28@@oe@16-12-2010 880443705@GENIA Treebank@formal@@1@S@The variant Id-3L protein is functionally distinguishable from conventional Id-3 since in in vitro DNA mobility shift assays, it was greatly impaired in its ability to abrogate binding of the basic helix-loop-helix protein, E47, to an E box recognition sequence.@@@@1@44@@oe@16-12-2010 880563001@GENIA Treebank@formal@@1@S@Multifactor cis-dominant negative regulation of IL-2 gene expression in anergized T cells.@@@@1@13@@oe@16-12-2010 880563002@GENIA Treebank@formal@@1@S@The molecular mechanism underlying IL-2 transcriptional blockade in anergic T cell clones is not fully understood.@@@@1@17@@oe@16-12-2010 880563003@GENIA Treebank@formal@@1@S@To examine whether an active negative regulatory process occurs, we created a reporter construct containing as an enhancer four copies of the NF-AT site and one copy of the octamer site (4X NF-AT-Oct).@@@@1@37@@oe@16-12-2010 880563004@GENIA Treebank@formal@@1@S@This construct was only slightly reduced (1.3-fold) in its expression when stimulated under anergic conditions, while a whole mouse IL-2 enhancer construct showed a reduction of 4.3-fold.@@@@1@31@@oe@16-12-2010 880563005@GENIA Treebank@formal@@1@S@Addition of the -176 to -96 sequence to the 4X NF-AT-Oct construct did not impart the ability to be affected by anergy, but addition of the -236 to -96 sequence did, demonstrating that anergy is an active inhibitory process and that more than the presence of the -150 AP-1 binding site (-152 to -147) is required to mediate the effect.@@@@1@65@@oe@16-12-2010 880563006@GENIA Treebank@formal@@1@S@Mutational studies of the -236 to -96 sequence indicated that the presence of both the -130 AP-1-like site (-187 to -181) and the -150 proximal AP-1 site were necessary to observe anergy.@@@@1@35@@oe@16-12-2010 880563007@GENIA Treebank@formal@@1@S@Because the -180 site is not required for trans-activation, it was possible to confirm by mutation in the normal mouse IL-2 enhancer that this site is absolutely essential for anergy induction.@@@@1@33@@oe@16-12-2010 880563008@GENIA Treebank@formal@@1@S@The simplest model to explain these results is that anergy is mediated by a complex of multiple transcription factors that exert a cis-acting dominant negative regulatory effect on the trans-activation of the IL-2 gene.@@@@1@35@@oe@16-12-2010 880911101@GENIA Treebank@formal@@1@S@Characterization of the human myeloid cell nuclear differentiation antigen gene promoter.@@@@1@12@@oe@16-12-2010 880911102@GENIA Treebank@formal@@1@S@MNDA (myeloid cell nuclear differentiation antigen) is an interferon alpha regulated nuclear protein expressed only in cells of the human myelomonocytic lineage.@@@@1@25@@oe@16-12-2010 880911103@GENIA Treebank@formal@@1@S@To identify mechanisms responsible for this lineage-specific and interferon-regulated expression, the 5' flanking sequence of the gene has been characterized.@@@@1@22@@oe@16-12-2010 880911104@GENIA Treebank@formal@@1@S@Two interferon-stimulated response elements (ISRE) flank a multiple transcription start site region identifying MNDA as a TATA-less interferon-regulated gene.@@@@1@22@@oe@16-12-2010 880911105@GENIA Treebank@formal@@1@S@Other DNA elements present include a cluster of Myb sites, several Ets, an Ets related PU.1 site and an Sp1 site located within 600 bp of the transcription start sites.@@@@1@33@@oe@16-12-2010 880911106@GENIA Treebank@formal@@1@S@In addition, DNA methylation was revealed as one of the possible factors in establishing MNDA expression.@@@@1@18@@oe@16-12-2010 880911107@GENIA Treebank@formal@@1@S@The 5' flanking sequence has promoter activity which is elevated by interferon alpha.@@@@1@14@@oe@16-12-2010 880911108@GENIA Treebank@formal@@1@S@The findings indicate that MNDA expression is regulated by mechanisms similar to other myelomonocytic cell specific genes and genes up-regulated by interferon alpha.@@@@1@24@@oe@16-12-2010 880940901@GENIA Treebank@formal@@1@S@Regulation of GM-CSF gene transcription by core-binding factor.@@@@1@9@@oe@16-12-2010 880940902@GENIA Treebank@formal@@1@S@GM-CSF gene activation in T cells is known to involve the transcription factors nuclear factor-kappa B, AP-1, NFAT, and Sp1.@@@@1@24@@oe@16-12-2010 880940903@GENIA Treebank@formal@@1@S@Here we demonstrate that the human GM-CSF promoter and enhancer also encompass binding sites for core-binding factor (CBF).@@@@1@21@@oe@16-12-2010 880940904@GENIA Treebank@formal@@1@S@Significantly, the CBF sites are in each case contained within the minimum essential core regions required for inducible activation of transcription.@@@@1@23@@oe@16-12-2010 880940905@GENIA Treebank@formal@@1@S@Furthermore, these core regions of the enhancer and promoter each encompass closely linked binding sites for CBF, AP-1, and NFATp.@@@@1@24@@oe@16-12-2010 880940906@GENIA Treebank@formal@@1@S@The GM-CSF promoter CBF site TGTGGTCA is located 51 bp upstream of the transcription start site and also overlaps a YY-1 binding site.@@@@1@24@@oe@16-12-2010 880940907@GENIA Treebank@formal@@1@S@A 2-bp mutation within the CBF site resulted in a 2-3-fold decrease in the activities of both a 69-bp proximal promoter fragment and a 627-bp full-length promoter fragment.@@@@1@29@@oe@16-12-2010 880940908@GENIA Treebank@formal@@1@S@Stepwise deletions into the proximal promoter also revealed that the CBF site, but not the YY-1 site, was required for efficient induction of transcriptional activation.@@@@1@28@@oe@16-12-2010 880940909@GENIA Treebank@formal@@1@S@The AML1 and CBF beta genes that encode CBF each have the ability to influence cell growth and differentiation and have been implicated as proto-oncogenes in acute myeloid leukemia.@@@@1@30@@oe@16-12-2010 880940910@GENIA Treebank@formal@@1@S@This study adds GM-CSF to a growing list of cytokines and receptors that are regulated by CBF and which control the growth, differentiation, and activation of hemopoietic cells.@@@@1@31@@oe@16-12-2010 880940911@GENIA Treebank@formal@@1@S@The GM-CSF locus may represent one of several target genes that are dysregulated in acute myeloid leukemia.@@@@1@18@@oe@16-12-2010 880947201@GENIA Treebank@formal@@1@S@Mechanisms that contribute to the development of lymphoid malignancies: roles for genetic alterations and cytokine production.@@@@1@18@@oe@16-12-2010 880947202@GENIA Treebank@formal@@1@S@Recent studies have defined genetic alterations commonly associated with transformed lymphocytes.@@@@1@12@@oe@16-12-2010 880947203@GENIA Treebank@formal@@1@S@This review suggests roles for these alterations in the development of lymphoid neoplasms.@@@@1@14@@oe@16-12-2010 880947204@GENIA Treebank@formal@@1@S@Damage to the genes encoding proteins that function in intracellular signaling, transcription, or regulation of the cell cycle has been identified and linked at varying degrees to the progression of certain lymphoid malignancies.@@@@1@36@@oe@16-12-2010 880947205@GENIA Treebank@formal@@1@S@An understanding of the mechanistic consequences following such genetic alterations is essential to an understanding of the development of these lymphoid neoplasms.@@@@1@23@@oe@16-12-2010 880947206@GENIA Treebank@formal@@1@S@In contrast, it is also becoming clear that the dysregulated expression of proteins that are not genetically altered can also contribute to the progression of lymphoid malignancies.@@@@1@29@@oe@16-12-2010 880947207@GENIA Treebank@formal@@1@S@One such example is the excessive expression of "normal" lymphokines of cytokines which accompanies many lymphoproliferative diseases.@@@@1@20@@oe@16-12-2010 880947208@GENIA Treebank@formal@@1@S@The dysregulated expression of cytokines during malignancy can result in the augmentation of growth of transformed lymphocytes, as well as an alteration of the anti-tumor immune response.@@@@1@29@@oe@16-12-2010 880947209@GENIA Treebank@formal@@1@S@The latter mechanism is especially important because evasion of the impending immune response is a prerequisite for the progression of lymphoproliferative diseases.@@@@1@23@@oe@16-12-2010 880947210@GENIA Treebank@formal@@1@S@Taken together, this review supports the notion that the development of lymphoid malignancies is multifactorial, involving genetic alterations as well as dysregulated cytokine expression.@@@@1@27@@oe@16-12-2010 881061901@GENIA Treebank@formal@@1@S@Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum.@@@@1@19@@oe@16-12-2010 881061902@GENIA Treebank@formal@@1@S@Cystic fibrosis (CF) patients develop progressive cytokine-mediated inflammatory lung disease, with abundant production of thick, tenacious, protease- and oxidant-rich purulent airway secretions that are difficult to clear even with physiotherapy.@@@@1@36@@oe@16-12-2010 881061903@GENIA Treebank@formal@@1@S@In the search for a potential treatment, we have tested tyloxapol, an alkylaryl polyether alcohol polymer detergent previously used as a mucolytic agent in adult chronic bronchitis.@@@@1@30@@oe@16-12-2010 881061904@GENIA Treebank@formal@@1@S@Tyloxapol inhibits activation of the transcription factor nuclear factor-kappa B (NK-kappa B), reduces resting secretion of the cytokine interleukin-8 (IL-8) in cultured human monocytes, and inhibits lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the eiconsanoids thromboxane A2 and leukotriene B4 (LTB4).@@@@1@72@@oe@16-12-2010 881061905@GENIA Treebank@formal@@1@S@We have previously shown that tyloxapol is a potent antioxidant for hydroxyl radicals ( OH).@@@@1@17@@oe@16-12-2010 881061906@GENIA Treebank@formal@@1@S@Tyloxapol (0.05 to 0.1% wt/vol) effectively scavenges the oxidant hypochlorous acid (HOCl; 1 to 7.5 mM) in vitro, and protects from HOCl-mediated lung injury in rats.@@@@1@34@@oe@16-12-2010 881061907@GENIA Treebank@formal@@1@S@Tyloxapol also reduces the viscosity of CF sputum (from 463 +/- 133 to 128 +/- 52 centipoise).@@@@1@20@@oe@16-12-2010 881061908@GENIA Treebank@formal@@1@S@We conclude that tyloxapol is potentially useful as a new antiinflammatory therapy for CF lung disease, and could possibly promote clearance of secretions in the CF airway.@@@@1@29@@oe@16-12-2010 881423801@GENIA Treebank@formal@@1@S@Abnormality of Oct-1 DNA binding in T cells from Sjogren's syndrome patients.@@@@1@14@@oe@16-12-2010 881423802@GENIA Treebank@formal@@1@S@Primary Sjogren's syndrome (SS) is an autoimmune rheumatic disease characterized by T cell hypoactivity.@@@@1@18@@oe@16-12-2010 881423803@GENIA Treebank@formal@@1@S@To understand the diminished T cell response to activation signals, we measured nucleoprotein DNA-binding activities regulating gene expression during T cell activation using the electrophoretic mobility shift assay.@@@@1@30@@oe@16-12-2010 881423804@GENIA Treebank@formal@@1@S@Peripheral blood lymphocytes from 9/19 SS patients were found to be defective in their ability to bind an october sequence (Oct-1).@@@@1@24@@oe@16-12-2010 881423805@GENIA Treebank@formal@@1@S@This Oct-1-binding phenotype remained stable in culture for up to 3 days prior to activation.@@@@1@16@@oe@16-12-2010 881423806@GENIA Treebank@formal@@1@S@This abnormality was not seen in resting T cells nor T cells from patients with systemic lupus erythematosus, rheumatoid arthritis (RA), or SS accompanied by RA.@@@@1@31@@oe@16-12-2010 881423807@GENIA Treebank@formal@@1@S@The SS Oct-1 DNA-binding abnormality correlated significantly with an inability of cells to exit the Gzero/G1 cell cycle phase when stimulated in vitro.@@@@1@24@@oe@16-12-2010 881423808@GENIA Treebank@formal@@1@S@Importantly, nucleoprotein extracts showing decreased DNA-binding activity had normal amounts of Oct-1 proteins as determined by immunoprecipitation, implying a functional defect in the Oct-1 protein.@@@@1@28@@oe@16-12-2010 881423809@GENIA Treebank@formal@@1@S@Moreover, defective DNA binding was corrected by treatment with acid phosphatase.@@@@1@13@@oe@16-12-2010 881425601@GENIA Treebank@formal@@1@S@Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings.@@@@1@23@@oe@16-12-2010 881425602@GENIA Treebank@formal@@1@S@Peripheral blood lymphocytes (PBL) and alloreactive T cell lines of two male infants born to consanguinous parents and presenting with severe combined immunodeficiency (SCID) showed a pronounced deficiency in T cell activation.@@@@1@37@@oe@16-12-2010 881425603@GENIA Treebank@formal@@1@S@Although phenotypically normal, the proliferative response of the childrens' T cells was strongly reduced but could be improved by the addition of interleukin-2 (IL-2).@@@@1@29@@oe@16-12-2010 881425604@GENIA Treebank@formal@@1@S@Furthermore both childrens' T cells were unable to produce the cytokines IL-2, interferon-gamma (IFN-gamma), IL-4 and tumor necrosis factor-alpha (TNF-alpha).@@@@1@28@@oe@16-12-2010 881425605@GENIA Treebank@formal@@1@S@This multiple cytokine production deficiency could not be restored by IL-2 or co-stimulatory signals provided by antigen-presenting cells (APC).@@@@1@22@@oe@16-12-2010 881425606@GENIA Treebank@formal@@1@S@Moreover, mRNA for IL-2 and IFN-gamma could not be detected.@@@@1@12@@oe@16-12-2010 881425607@GENIA Treebank@formal@@1@S@In contrast, expression of the activation-dependent cell surface markers CD25 and CD69 was within normal limits.@@@@1@18@@oe@16-12-2010 881425608@GENIA Treebank@formal@@1@S@To determine whether the functional defect of the patients' T cells was due to the absence or abnormal binding of transcription factors involved in cytokine gene expression, electrophoretic mobility shift assays were used to examine the DNA binding of AP-1, Oct, CREB, SP1, NF-kappa B and the nuclear factor of activated T cells (NF-AT) to their respective response elements in the promoter of the IL-2 gene.@@@@1@75@@oe@16-12-2010 881425609@GENIA Treebank@formal@@1@S@Whereas AP-1, NF-kappa B, Oct, CREB and SP1 displayed normal binding activities in nuclear extracts, the binding of NF-AT to its IL-2 promoter response element was barely detectable both before and after T cell stimulation.@@@@1@40@@oe@16-12-2010 881425610@GENIA Treebank@formal@@1@S@Our results strongly suggest that this NF-AT/DNA binding defect is responsible for the multiple cytokine deficiency and the SCID phenotype observed in the two infant brothers.@@@@1@27@@oe@16-12-2010 881639501@GENIA Treebank@formal@@1@S@Requirements for induction of vitamin D-mediated gene regulation in normal human B lymphocytes.@@@@1@14@@oe@16-12-2010 881639502@GENIA Treebank@formal@@1@S@Mature human lymphocytes are unique targets of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) in that vitamin D receptors (VDR) are not constitutively expressed, and specific cellular activation signals are required for both the up-regulation of VDR and establishment of reactivity to the lipophilic ligand.@@@@1@49@@oe@16-12-2010 881639503@GENIA Treebank@formal@@1@S@Treatment of B lymphocytes with the cytokine IL-4 (IL-4), in the absence of prior activation, induces a weak up-regulation of VDR expression but fails to generate vitamin D-responsive element (VDRE)-reactive nuclear protein complexes or to initiate the genomic transcription of 25-hydroxyvitamin D3 24-hydroxylase.@@@@1@51@@oe@16-12-2010 881639504@GENIA Treebank@formal@@1@S@Stimulation of B lymphocytes by either ligation of CD40 Ag or cross-linking the Ig receptor is also insufficient to render B lymphocytes responsive to 1 alpha,25(OH)2D3.@@@@1@27@@oe@16-12-2010 881639505@GENIA Treebank@formal@@1@S@However, this apparent lack of response to the secosterol can be overcome by stimulation of B lymphocytes with a combination of these cellular activation signals, which are sufficient to lead to G1 cell cycle progression.@@@@1@38@@oe@16-12-2010 881639506@GENIA Treebank@formal@@1@S@In the presence of 1 alpha,25(OH)2D3, cellular activation associated with stimulation of such a progression appears to be sufficient for the up-regulation of VDR message and protein and necessary for the establishment of VDRE binding complexes and the induction of 24-hydroxylase message.@@@@1@44@@oe@16-12-2010 881639507@GENIA Treebank@formal@@1@S@Furthermore, biologic functions are modulated, in that the hormone inhibits proliferation in a subset of the activated B cells.@@@@1@22@@oe@16-12-2010 881639508@GENIA Treebank@formal@@1@S@These observations suggest that reactivity to 1 alpha,25(OH)2D3 is tightly regulated in B lymphocytes, requiring specific signals for its initiation.@@@@1@22@@oe@16-12-2010 881642401@GENIA Treebank@formal@@1@S@Regulation of sialoadhesin expression on rat macrophages.@@@@1@8@@oe@16-12-2010 881642402@GENIA Treebank@formal@@1@S@Induction by glucocorticoids and enhancement by IFN-beta, IFN-gamma, IL-4, and lipopolysaccharide.@@@@1@15@@oe@16-12-2010 881642403@GENIA Treebank@formal@@1@S@Sialoadhesin is a macrophage-restricted member of the Ig superfamily that mediates adhesion with lymphoid and myeloid cells.@@@@1@18@@oe@16-12-2010 881642404@GENIA Treebank@formal@@1@S@It is expressed on a subpopulation of macrophages in lymphoid tissues and in chronic inflammation (e.g., during autoimmune diseases).@@@@1@23@@oe@16-12-2010 881642405@GENIA Treebank@formal@@1@S@We have studied the regulation of sialoadhesin expression in vitro and show that glucocorticoids (GC) induce sialoadhesin expression on freshly isolated rat macrophages and the rat macrophage cell line R2.@@@@1@33@@oe@16-12-2010 881642406@GENIA Treebank@formal@@1@S@The cytokines IFN-beta, IFN-gamma, IL-4, and LPS, although unable to induce sialoadhesin expression by themselves, were able to enhance GC-mediated induction of sialoadhesin.@@@@1@29@@oe@16-12-2010 881642407@GENIA Treebank@formal@@1@S@Sialoadhesin expression was functional as shown by cell adhesion assays with human RBCs.@@@@1@14@@oe@16-12-2010 881642408@GENIA Treebank@formal@@1@S@Northern blotting experiments indicated that regulation predominantly occurred at the mRNA level.@@@@1@13@@oe@16-12-2010 881642409@GENIA Treebank@formal@@1@S@Comparison of the different combinations of GC and cytokines/LPS revealed differences in the level of GC-dependent enhancement of sialoadhesin expression, with IFN-beta and IL-4 being more potent than IFN-gamma and LPS.@@@@1@33@@oe@16-12-2010 881642410@GENIA Treebank@formal@@1@S@Moreover, the effects of IFN-gamma and LPS could be reproduced by priming, whereas IFN-beta and IL-4 were required simultaneously with GC.@@@@1@24@@oe@16-12-2010 881642411@GENIA Treebank@formal@@1@S@The regulation of sialoadhesin expression was mediated by the GC receptor, and not by mineralocorticoid receptor, as shown by inhibition experiments with specific antagonists.@@@@1@27@@oe@16-12-2010 881642412@GENIA Treebank@formal@@1@S@Finally, it is demonstrated that macrophages in the adrenal gland, the major site of endogenous GC production, express sialoadhesin.@@@@1@23@@oe@16-12-2010 881642413@GENIA Treebank@formal@@1@S@This study demonstrates that GC act as a primary inducer of sialoadhesin expression on rat macrophages, and that the response can be enhanced by IFN-beta, T cell-derived cytokines, or LPS.@@@@1@34@@oe@16-12-2010 881643601@GENIA Treebank@formal@@1@S@Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN.@@@@1@21@@oe@16-12-2010 881643602@GENIA Treebank@formal@@1@S@The human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest genes transcribed after the stimulation of a B cell through its antigen receptor or via the CD-40 pathway.@@@@1@34@@oe@16-12-2010 881643603@GENIA Treebank@formal@@1@S@In both cases, induction of TNF-alpha gene transcription can be blocked by the immunosuppressants cyclosporin A and FK506, which suggested a role for the NFAT family of proteins in the regulation of the gene in B cells.@@@@1@40@@oe@16-12-2010 881643604@GENIA Treebank@formal@@1@S@Furthermore, in T cells, two molecules of NFATp bind to the TNF-alpha promoter element kappa 3 in association with ATF-2 and Jun proteins bound to an immediately adjacent cyclic AMP response element (CRE) site.@@@@1@39@@oe@16-12-2010 881643605@GENIA Treebank@formal@@1@S@Here, using the murine B-cell lymphoma cell line A20, we show that the TNF-alpha gene is regulated in a cell-type-specific manner.@@@@1@24@@oe@16-12-2010 881643606@GENIA Treebank@formal@@1@S@In A20 B cells, the TNF-alpha gene is not regulated by NFATp bound to the kappa 3 element.@@@@1@20@@oe@16-12-2010 881643607@GENIA Treebank@formal@@1@S@Instead, ATF-2 and Jun proteins bind to the composite kappa 3/CRE site and NFATp binds to a newly identified second NFAT site centered at -76 nucleotides relative to the TNF-alpha transcription start site.@@@@1@35@@oe@16-12-2010 881643608@GENIA Treebank@formal@@1@S@This new site plays a critical role in the calcium-mediated, cyclosporin A-sensitive induction of TNF-alpha in both A20 B cells and Ar-5 cells.@@@@1@25@@oe@16-12-2010 881643609@GENIA Treebank@formal@@1@S@Consistent with these results, quantitative DNase footprinting of the TNF-alpha promoter using increasing amounts of recombinant NFATp demonstrated that the -76 site binds to NFATp with a higher affinity than the kappa 3 site.@@@@1@36@@oe@16-12-2010 881643610@GENIA Treebank@formal@@1@S@Two other previously unrecognized NFATp-binding sites in the proximal TNF-alpha promoter were also identified by this analysis.@@@@1@18@@oe@16-12-2010 881643611@GENIA Treebank@formal@@1@S@Thus, through the differential use of the same promoter element, the composite kappa 3/CRE site, the TNF-alpha gene is regulated in a cell-type-specific manner in response to the same extracellular signal.@@@@1@35@@oe@16-12-2010 881645001@GENIA Treebank@formal@@1@S@Analysis of the ligand-binding domain of human retinoic acid receptor alpha by site-directed mutagenesis.@@@@1@15@@oe@16-12-2010 881645002@GENIA Treebank@formal@@1@S@Three subtypes of retinoic acid receptors (RAR), termed RAR alpha, RAR beta, and RAR gamma, have been described.@@@@1@25@@oe@16-12-2010 881645003@GENIA Treebank@formal@@1@S@They are composed of different structural domains, including distinct domains for DNA and ligand binding.@@@@1@17@@oe@16-12-2010 881645004@GENIA Treebank@formal@@1@S@RARs specifically bind all-trans-retinoic acid (RA), 9-cis-RA, and retinoid analogs.@@@@1@15@@oe@16-12-2010 881645005@GENIA Treebank@formal@@1@S@In this study, we examined the functional role of cysteine and arginine residues in the ligand-binding domain of hRAR alpha (hRAR alpha-LBD, amino acids 154 to 462).@@@@1@32@@oe@16-12-2010 881645006@GENIA Treebank@formal@@1@S@All conserved cysteine and arginine residues in this domain were mutated by site-directed mutagenesis, and the mutant proteins were characterized by blocking reactions, ligand-binding experiments, transactivation assays, and protease mapping.@@@@1@35@@oe@16-12-2010 881645007@GENIA Treebank@formal@@1@S@Changes of any cysteine residue of the hRAR alpha-LBD had no significant influence on the binding of all-trans RA or 9-cis RA.@@@@1@23@@oe@16-12-2010 881645008@GENIA Treebank@formal@@1@S@Interestingly, residue C-235 is specifically important in antagonist binding.@@@@1@11@@oe@16-12-2010 881645009@GENIA Treebank@formal@@1@S@With respect to arginine residues, only the two single mutations of R-276 and R-394 to alanine showed a dramatic decrease of agonist and antagonist binding whereas the R272A mutation showed only a slight effect.@@@@1@36@@oe@16-12-2010 881645010@GENIA Treebank@formal@@1@S@For all other arginine mutations, no differences in affinity were detectable.@@@@1@13@@oe@16-12-2010 881645011@GENIA Treebank@formal@@1@S@The two mutations R217A and R294A caused an increased binding efficiency for antagonists but no change in agonist binding.@@@@1@20@@oe@16-12-2010 881645012@GENIA Treebank@formal@@1@S@From these results, we can conclude that electrostatic interactions of retinoids with the RAR alpha-LBD play a significant role in ligand binding.@@@@1@24@@oe@16-12-2010 881645013@GENIA Treebank@formal@@1@S@In addition, antagonists show distinctly different requirements for efficient binding, which may contribute to their interference in the ligand-inducible transactivation function of RAR alpha.@@@@1@27@@oe@16-12-2010 881645401@GENIA Treebank@formal@@1@S@Cloning and characterization of the beta subunit of human proximal sequence element-binding transcription factor and its involvement in transcription of small nuclear RNA genes by RNA polymerases II and III.@@@@1@31@@oe@16-12-2010 881645402@GENIA Treebank@formal@@1@S@The proximal sequence element (PSE)-binding transcription factor (PTF), which binds the PSE of both RNA polymerase II- and RNA polymerase III-transcribed mammalian small nuclear RNA (snRNA) genes, is essential for their transcription.@@@@1@42@@oe@16-12-2010 881645403@GENIA Treebank@formal@@1@S@We previously reported the purification of human PTF, a complex of four subunits, and the molecular cloning and characterization of PTF gamma and delta subunits.@@@@1@28@@oe@16-12-2010 881645404@GENIA Treebank@formal@@1@S@Here we describe the isolation and expression of a cDNA encoding PTF beta, as well as functional studies using anti-PTF beta antibodies.@@@@1@24@@oe@16-12-2010 881645405@GENIA Treebank@formal@@1@S@Native PTF beta, in either protein fractions or a PTF-Oct-1-DNA complex, can be recognized by polyclonal antibodies raised against recombinant PTF beta.@@@@1@25@@oe@16-12-2010 881645406@GENIA Treebank@formal@@1@S@Immunodepletion studies show that PTF beta is required for transcription of both classes of snRNA genes in vitro.@@@@1@19@@oe@16-12-2010 881645407@GENIA Treebank@formal@@1@S@In addition, immunoprecipitation analyses demonstrate that substantial and similar molar amounts of TATA-binding protein (TBP) and TFIIIB90 can weakly associate with PTF at low salt conditions, but this association is dramatically reduced at high salt concentrations.@@@@1@41@@oe@16-12-2010 881645408@GENIA Treebank@formal@@1@S@Along with our previous demonstration of both physical interactions between PTF gamma/PTF delta and TBP and the involvement of TFIIIB90 in the transcription of class III snRNA genes, these results are consistent with the notion that a TBP-containing complex related to TFIIIB is required for the transcription of class III snRNA genes, and acts through weak interaction with the four-subunit PTF.@@@@1@66@@oe@16-12-2010 881646701@GENIA Treebank@formal@@1@S@Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis.@@@@1@16@@oe@16-12-2010 881646702@GENIA Treebank@formal@@1@S@Engagement of surface immunoglobulin on mature B cells leads to rescue from apoptosis and to proliferation.@@@@1@17@@oe@16-12-2010 881646703@GENIA Treebank@formal@@1@S@Levels of bcl-2 mRNA and protein increase with cross-linking of surface immunoglobulin.@@@@1@13@@oe@16-12-2010 881646704@GENIA Treebank@formal@@1@S@We have located the major positive regulatory region for control of bcl-2 expression in B cells in the 5'-flanking region.@@@@1@21@@oe@16-12-2010 881646705@GENIA Treebank@formal@@1@S@The positive region can be divided into an upstream and a downstream regulatory region.@@@@1@15@@oe@16-12-2010 881646706@GENIA Treebank@formal@@1@S@The downstream regulatory region contains a cyclic AMP-responsive element (CRE).@@@@1@13@@oe@16-12-2010 881646707@GENIA Treebank@formal@@1@S@We show by antibody supershift experiments and UV cross-linking followed by denaturing polyacrylamide gel electrophoresis that both CREB and ATF family members bind to this region in vitro.@@@@1@29@@oe@16-12-2010 881646708@GENIA Treebank@formal@@1@S@Mutations of the CRE site that result in loss of CREB binding also lead to loss of functional activity of the bcl-2 promoter in transient-transfection assays.@@@@1@27@@oe@16-12-2010 881646709@GENIA Treebank@formal@@1@S@The presence of an active CRE site in the bcl-2 promoter implies that the regulation of bcl-2 expression is linked to a signal transduction pathway in B cells.@@@@1@29@@oe@16-12-2010 881646710@GENIA Treebank@formal@@1@S@Treatment of the mature B-cell line BAL-17 with either anti-immunoglobulin M or phorbol 12-myristate 13-acetate leads to an increase in bcl-2 expression that is mediated by the CRE site.@@@@1@30@@oe@16-12-2010 881646711@GENIA Treebank@formal@@1@S@Treatment of the more immature B-cell line, Ramos, with phorbol esters rescues the cells from calcium-dependent apoptosis.@@@@1@20@@oe@16-12-2010 881646712@GENIA Treebank@formal@@1@S@bcl-2 expression is increased following phorbol ester treatment, and the increased expression is dependent on the CRE site.@@@@1@20@@oe@16-12-2010 881646713@GENIA Treebank@formal@@1@S@These stimuli result in phosphorylation of CREB at serine 133.@@@@1@11@@oe@16-12-2010 881646714@GENIA Treebank@formal@@1@S@The phosphorylation of CREB that results in activation is mediated by protein kinase C rather than by protein kinase A.@@@@1@21@@oe@16-12-2010 881646715@GENIA Treebank@formal@@1@S@Although the CRE site is necessary, optimal induction of bcl-2 expression requires participation of the upstream regulatory element, suggesting that phosphorylation of CREB alters its interaction with the upstream regulatory element.@@@@1@34@@oe@16-12-2010 881646716@GENIA Treebank@formal@@1@S@The CRE site in the bcl-2 promoter appears to play a major role in the induction of bcl-2 expression during the activation of mature B cells and during the rescue of immature B cells from apoptosis.@@@@1@37@@oe@16-12-2010 881646717@GENIA Treebank@formal@@1@S@It is possible that the CRE site is responsible for induction of bcl-2 expression in other cell types, particularly those in which protein kinase C is involved.@@@@1@29@@oe@16-12-2010 882294201@GENIA Treebank@formal@@1@S@Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein.@@@@1@12@@oe@16-12-2010 882294202@GENIA Treebank@formal@@1@S@Interleukin-6 (IL-6) mediates autocrine and paracrine growth of multiple myeloma (MM) cells and inhibits tumor cell apoptosis.@@@@1@22@@oe@16-12-2010 882294203@GENIA Treebank@formal@@1@S@Abnormalities of retinoblastoma protein (pRB) and mutations of RB gene have been reported in up to 70% of MM patients and 80% of MM-derived cell lines.@@@@1@31@@oe@16-12-2010 882294204@GENIA Treebank@formal@@1@S@Because dephosphorylated (activated) pRB blocks transition from G1 to S phase of the cell cycle whereas phosphorylated (inactivated) pRB releases this growth arrest, we characterized the role of pRB in IL-6-mediated MM cell growth.@@@@1@40@@oe@16-12-2010 882294205@GENIA Treebank@formal@@1@S@Both phosphorylated and dephosphorylated pRB were expressed in all serum-starved MM patient cells and MM-derived cell lines, but pRB was predominantly in its phosphorylated form.@@@@1@27@@oe@16-12-2010 882294206@GENIA Treebank@formal@@1@S@In MM cells that proliferated in response to IL-6, exogenous IL-6 downregulated dephosphorylated pRB and decreased dephosphorylated pRB-E2F complexes.@@@@1@21@@oe@16-12-2010 882294207@GENIA Treebank@formal@@1@S@Importantly, culture of MM cells with RB antisense, but not RB sense, oligonucleotide (ODN) triggered IL-6 secretion and proliferation in MM cells; however, proliferation was only partially inhibited by neutralizing anti-IL-6 monoclonal antibody (MoAb).@@@@1@44@@oe@16-12-2010 882294208@GENIA Treebank@formal@@1@S@In contrast to MM cells, normal splenic B cells express dephosphorylated pRB.@@@@1@14@@oe@16-12-2010 882294209@GENIA Treebank@formal@@1@S@Although CD40 ligand (CD40L) triggers a shift from dephosphorylated to phosphorylated pRB and proliferation of B cells, the addition of exogenous IL-6 to CD40L-treated B cells does not alter either pRB or proliferation, as observed in MM cells.@@@@1@43@@oe@16-12-2010 882294210@GENIA Treebank@formal@@1@S@These results suggest that phosphorylated pRB is constitutively expressed in MM cells and that IL-6 further shifts pRB from its dephosphorylated to its phosphorylated form, thereby promoting MM cell growth via two mechanisms; by decreasing the amount of E2F bound by dephosphorylated pRB due to reduced dephosphorylated pRB, thereby releasing growth arrest; and by upregulating IL-6 secretion by MM cells and related IL-6-mediated autocrine tumor cell growth.@@@@1@72@@oe@16-12-2010 882428701@GENIA Treebank@formal@@1@S@JNK (c-Jun NH2-terminal kinase) is a target for antioxidants in T lymphocytes.@@@@1@15@@oe@16-12-2010 882428702@GENIA Treebank@formal@@1@S@AP-1 has been shown to behave as a redox-sensitive transcription factor that can be activated by both oxidant and antioxidant stimuli.@@@@1@22@@oe@16-12-2010 882428703@GENIA Treebank@formal@@1@S@However, the mechanisms involved in the activation of AP-1 by antioxidants are largely unknown.@@@@1@16@@oe@16-12-2010 882428704@GENIA Treebank@formal@@1@S@In this study we show that the structurally unrelated antioxidant agents pyrrolidine dithiocarbamate (PDTC), butylated hydroxyanisole, and Nacetylcysteine activated JNK (c-Jun NH2-terminal kinase) in Jurkat T cells.@@@@1@34@@oe@16-12-2010 882428705@GENIA Treebank@formal@@1@S@This activation differed substantially from that mediated by phorbol 12-myristate 13-acetate (PMA) and Ca2+ ionophore or produced by costimulation with antibodies against the T cell receptor-CD3 complex and to CD28.@@@@1@33@@oe@16-12-2010 882428706@GENIA Treebank@formal@@1@S@The activation of JNK by classical T cell stimuli was transient, whereas that mediated by PDTC and butylated hydroxyanisole (but not N-acetylcysteine) was sustained.@@@@1@28@@oe@16-12-2010 882428707@GENIA Treebank@formal@@1@S@The kinetics of JNK activation correlated with the expression of c-jun which was transient after stimulation with PMA plus ionophore and prolonged in response to PDTC, which also transiently induced c-fos.@@@@1@33@@oe@16-12-2010 882428708@GENIA Treebank@formal@@1@S@In addition, JNK activation by PMA plus ionophore was sensitive to inhibitors of signaling pathways involving Ca2+, protein kinase C, and tyrosine phosphorylation, which failed to inhibit the activation mediated by PDTC.@@@@1@37@@oe@16-12-2010 882428709@GENIA Treebank@formal@@1@S@Transfection of trans-dominant negative expression vectors of ras and raf, together with AP-1-dependent reporter constructs, as well as Western blot analysis using anti-ERK (extracellular signal-regulated kinase) antibodies, indicated that the Ras/Raf/ERK pathway did not appear to mediate the effect of the antioxidant.@@@@1@48@@oe@16-12-2010 882428710@GENIA Treebank@formal@@1@S@However, the combined treatment with PDTC and PMA, two agents that synergize on AP-1 activation, resulted in the persistent phosphorylation of ERK-2.@@@@1@26@@oe@16-12-2010 882428711@GENIA Treebank@formal@@1@S@In conclusion, our results identify JNK as a target of antioxidant agents which can be regulated differentially under oxidant and antioxidant conditions.@@@@1@24@@oe@16-12-2010 883083201@GENIA Treebank@formal@@1@S@Cytomegalovirus modulates interleukin-6 gene expression.@@@@1@6@@oe@16-12-2010 883083202@GENIA Treebank@formal@@1@S@Complications after lung transplantation include the development of rejection and an increased incidence of infection, particularly with cytomegalovirus (CMV).@@@@1@23@@oe@16-12-2010 883083203@GENIA Treebank@formal@@1@S@Several recent studies have suggested that interleukin (IL)-6 may be used to detect both infection and rejection after lung transplantation.@@@@1@24@@oe@16-12-2010 883083204@GENIA Treebank@formal@@1@S@In addition, IL-6 may play a role in the development of bronchiolitis obliterans after transplantation.@@@@1@17@@oe@16-12-2010 883083205@GENIA Treebank@formal@@1@S@Because CMV is also associated with the development of bronchiolitis obliterans after transplantation, we determined whether CMV induces IL-6 gene expression.@@@@1@23@@oe@16-12-2010 883083206@GENIA Treebank@formal@@1@S@We demonstrated that CMV infection increased both IL-6 protein and mRNA in peripheral blood mononuclear cells.@@@@1@17@@oe@16-12-2010 883083207@GENIA Treebank@formal@@1@S@We also demonstrated that the CMV immediate early 1 gene product increased expression of the IL-6 promoter.@@@@1@18@@oe@16-12-2010 883083208@GENIA Treebank@formal@@1@S@This effect of the CMV immediate early 1 gene product was dependent upon the presence of specific transcription factor binding sites in the IL-6 promoter.@@@@1@26@@oe@16-12-2010 883083209@GENIA Treebank@formal@@1@S@These studies demonstrate that CMV may be an important cofactor in the development of rejection and infection after transplantation through its effects on IL-6.@@@@1@25@@oe@16-12-2010 883446401@GENIA Treebank@formal@@1@S@Suppression of the human immunodeficiency virus long terminal repeat by CD8+ T cells is dependent on the NFAT-1 element.@@@@1@20@@oe@16-12-2010 883446402@GENIA Treebank@formal@@1@S@CD8+ T lymphocytes of HIV-1 infected individuals produce a soluble factor that efficiently suppresses HIV-1 replication at the transcriptional level.@@@@1@21@@oe@16-12-2010 883446403@GENIA Treebank@formal@@1@S@We show here that the response of the HIV-1 long terminal repeat (LTR) to mitogenic or Tat-mediated activation is sensitive to the suppressive action of a Herpesvirus saimiri (HVS)-transformed CD8+ T cell clone from an HIV-infected individual and supernatants from CD8+ T cells of HIV-1-infected asymptomatic subjects (CD4+ > 350/microliters).@@@@1@58@@oe@16-12-2010 883446404@GENIA Treebank@formal@@1@S@Mutagenesis of NF kappa B or Sp-1 elements within the LTR resulted in no change in the ability of CD8+ T cell supernatants to inhibit Tat- or mitogen-mediated LTR transcription.@@@@1@31@@oe@16-12-2010 883446405@GENIA Treebank@formal@@1@S@However, the response to HIV-1 Tat by a LTR in which the interleukin (IL)-2 homology NFAT-1 region was mutated resulted in almost complete elimination of suppression by CD8+ T cells.@@@@1@35@@oe@16-12-2010 883446406@GENIA Treebank@formal@@1@S@This was not observed when the NFAT-1 mutant LTR was activated by mitogen.@@@@1@14@@oe@16-12-2010 883446407@GENIA Treebank@formal@@1@S@We have previously shown that gene expression directed by the HIV-1 NF kappa B elements is inhibited by CD8+ cell-derived supernatants (Copeland et al., AIDS Res Hum Retroviruses, 1995;11:1321-1326).@@@@1@38@@oe@16-12-2010 883446408@GENIA Treebank@formal@@1@S@Taken together, these observations suggest that mitogenic activation, mediated primarily through the NF kappa B enhancer, is susceptible to CD8-mediated inhibition, however, inhibition of Tat-mediated activation may rely upon a different pathway that is NFAT-1 dependent.@@@@1@42@@oe@16-12-2010 883984401@GENIA Treebank@formal@@1@S@E3, a hematopoietic-specific transcript directly regulated by the retinoic acid receptor alpha.@@@@1@14@@oe@16-12-2010 883984402@GENIA Treebank@formal@@1@S@Retinoic acid (RA)-induced maturation mediated by the retinoic acid receptor alpha (RAR alpha) has been implicated in myeloid development.@@@@1@25@@oe@16-12-2010 883984403@GENIA Treebank@formal@@1@S@We have used differential hybridization analysis of a cDNA library constructed from the murine RA-inducible MPRO promyelocyte cell line to identify immediate-early genes induced by RA during granulocytic differentiation.@@@@1@30@@oe@16-12-2010 883984404@GENIA Treebank@formal@@1@S@E3, one of nine sequences identified, was upregulated in an immediate-early manner, with transcript levels peaking after 60 minutes exposure to RA.@@@@1@26@@oe@16-12-2010 883984405@GENIA Treebank@formal@@1@S@E3 transcripts were RA-inducible in HL60 cells, but not in an RA-resistant subclone, HL60R, that harbors a mutated RAR alpha gene.@@@@1@25@@oe@16-12-2010 883984406@GENIA Treebank@formal@@1@S@However, when HL60R cells were transduced with a functional copy of the RAR alpha gene, RA induced a 10-fold increase in E3 mRNA levels.@@@@1@27@@oe@16-12-2010 883984407@GENIA Treebank@formal@@1@S@E3 transcripts are present in the myeloid, B-lymphoid, and erythroid lineages, absent in nonhematopoietic cells, and encode a highly hydrophobic, potentially phosphorylated polypeptide of unknown function with significant homology to a putative protein expressed in myeloid cells.@@@@1@43@@oe@16-12-2010 883984408@GENIA Treebank@formal@@1@S@The murine E3 promoter harbors a single bipartite retinoic acid response element which in transient transfection assays conferred RA sensitivity.@@@@1@21@@oe@16-12-2010 883984409@GENIA Treebank@formal@@1@S@These results indicate that E3 is a hematopoietic-specific gene that is an immediate target for the activated RAR alpha during myelopoiesis.@@@@1@22@@oe@16-12-2010 883986401@GENIA Treebank@formal@@1@S@Interstitial deletion constitutes the major mechanism for loss of heterozygosity on chromosome 20q in polycythemia vera.@@@@1@17@@oe@16-12-2010 883986402@GENIA Treebank@formal@@1@S@An acquired deletion of the long arm of chromosome 20 is a recurrent abnormality in myeloproliferative disorders, particularly polycythemia vera and myelodysplastic syndromes.@@@@1@25@@oe@16-12-2010 883986403@GENIA Treebank@formal@@1@S@The association of 20q deletions with myeloid "stem cell" disorders suggests that the deletions mark the site of one or more genes, loss or inactivation of which plays a role in the regulation of normal hematopoietic progenitors.@@@@1@41@@oe@16-12-2010 883986404@GENIA Treebank@formal@@1@S@We have recently performed a detailed molecular analysis of 20q deletions in peripheral blood (PB) granulocytes and defined a commonly deleted region of 16 to 21 centimorgan (cM).@@@@1@33@@oe@16-12-2010 883986405@GENIA Treebank@formal@@1@S@To further reduce the size of the common deleted region we have searched for small deletions or mitotic recombination events, neither of which would be detected by conventional cytogenetics.@@@@1@31@@oe@16-12-2010 883986406@GENIA Treebank@formal@@1@S@We have studied 48 patients with polycythemia vera and four patients with idiopathic myelofibrosis.@@@@1@15@@oe@16-12-2010 883986407@GENIA Treebank@formal@@1@S@In each case, cytogenetic analysis had either failed or had shown no abnormalities of chromosome 20.@@@@1@18@@oe@16-12-2010 883986408@GENIA Treebank@formal@@1@S@Seventeen microsatellite markers that span the common deleted region were used to search for loss of heterozygosity in granulocyte DNA.@@@@1@21@@oe@16-12-2010 883986409@GENIA Treebank@formal@@1@S@No instance of microsatellite instability was observed in a total of 880 comparisons of granulocyte and T-cell DNA.@@@@1@19@@oe@16-12-2010 883986410@GENIA Treebank@formal@@1@S@Granulocyte DNA from four patients exhibited allele loss on 20q.@@@@1@11@@oe@16-12-2010 883986411@GENIA Treebank@formal@@1@S@In each case the allele loss was caused by an interstitial deletion because heterozygosity at distal markers was retained and because quantitative Southern blotting demonstrated hemizygosity.@@@@1@27@@oe@16-12-2010 883986412@GENIA Treebank@formal@@1@S@Loss of heterozygosity in PB granulocytes would be masked by the presence of significant numbers of normal granulocytes not derived from the malignant clone.@@@@1@25@@oe@16-12-2010 883986413@GENIA Treebank@formal@@1@S@Therefore, the human androgen receptor assay (HUMARA) was used to determine granulocyte clonality.@@@@1@17@@oe@16-12-2010 883986414@GENIA Treebank@formal@@1@S@In 21 of 27 informative female patients the majority of the granulocytes were clonally derived.@@@@1@16@@oe@16-12-2010 883986415@GENIA Treebank@formal@@1@S@In 5 patients the granulocytes appeared polyclonal and in 1 patient unilateral X inactivation was observed in both granulocytes and T cells.@@@@1@23@@oe@16-12-2010 883986416@GENIA Treebank@formal@@1@S@These results show that, in the vast majority of patients presented here, the failure to detect loss of heterozygosity cannot be attributed to the presence of normal polyclonal granulocytes.@@@@1@33@@oe@16-12-2010 883986417@GENIA Treebank@formal@@1@S@Our results therefore show that allele loss on chromosome 20q in polycythemia vera does not commonly involve mitotic recombination or chromosome loss and that microsatellite instability is a rare event in this disorder.@@@@1@34@@oe@16-12-2010 884252501@GENIA Treebank@formal@@1@S@DNA-binding phosphoproteins induced after T cell activation: effects of cyclosporin A.@@@@1@13@@oe@16-12-2010 884252502@GENIA Treebank@formal@@1@S@To define novel proteins involved in the early transcriptional response during the activation of human T lymphocytes, we used a high-resolution, two-dimensional gel electrophoresis system to identify nuclear, deoxyribonucleic acid (DNA) binding proteins exhibiting rapid changes in phosphorylation following cell stimulation.@@@@1@47@@oe@16-12-2010 884252503@GENIA Treebank@formal@@1@S@We identified 18 nuclear proteins whose phosphorylation level changed more than 5-fold upon activation.@@@@1@15@@oe@16-12-2010 884252504@GENIA Treebank@formal@@1@S@Of these, 11 were found to possess DNA-binding properties.@@@@1@11@@oe@16-12-2010 884252505@GENIA Treebank@formal@@1@S@The 11 phosphoproteins with DNA-binding activity, along with 4 others, were analyzed further.@@@@1@16@@oe@16-12-2010 884252506@GENIA Treebank@formal@@1@S@Phosphoamino acid analysis revealed several sets of proteins with different phosphorylated residues Kinetic analysis of the phosphorylation of the selected proteins was performed and revealed a complex group of transient and sustained responses to cell activation.@@@@1@37@@oe@16-12-2010 884252507@GENIA Treebank@formal@@1@S@Finally, the activation-induced changes in one set of phosphoproteins were dramatically inhibited by cyclosporin A.@@@@1@17@@oe@16-12-2010 884252508@GENIA Treebank@formal@@1@S@We suggest that these phosphoproteins may be directly involved in regulating the transcriptional response to cellular activation by external stimuli.@@@@1@21@@oe@16-12-2010 884341301@GENIA Treebank@formal@@1@S@Transcriptional control of steroid-regulated apoptosis in murine thymoma cells.@@@@1@10@@oe@16-12-2010 884341302@GENIA Treebank@formal@@1@S@Early studies in murine T cell lines indicated that transcriptional transactivation functions encoded in the glucocorticoid receptor (GR) N-terminal domain are required for glucocorticoid-mediated apoptosis.@@@@1@28@@oe@16-12-2010 884341303@GENIA Treebank@formal@@1@S@However, more recent studies in human T cell lines have suggested that the N-terminal domain is not necessary for steroid-regulated apoptosis and that GR-mediated transrepression may be the more critical mechanism.@@@@1@33@@oe@16-12-2010 884341304@GENIA Treebank@formal@@1@S@To better understand the contribution of the GR N-terminal transactivation domain in mediating murine thymocyte apoptosis, we stably transfected GR, GR variants, and the androgen receptor (AR) into receptor-negative S49 murine thymoma cells.@@@@1@39@@oe@16-12-2010 884341305@GENIA Treebank@formal@@1@S@GR expression levels were shown to be rate-limiting for initiating the apoptotic pathway, and a positive correlation between steroid sensitivity and GR-mediated induction of an integrated mouse mammary tumor virus (MMTV) LTR reporter gene was observed.@@@@1@40@@oe@16-12-2010 884341306@GENIA Treebank@formal@@1@S@Analysis of GR chimeric receptors containing the potent VP16 and E1A viral transactivation domains in place of the GR N terminus revealed that even low level expression of these receptors resulted in both enhanced steroid sensitivity and MMTV induction, thus supporting a role for transactivation in apoptosis.@@@@1@49@@oe@16-12-2010 884341307@GENIA Treebank@formal@@1@S@In contrast, we found that AR can initiate apoptosis in S49 cells after treatment with 5 alpha-dihydrotestosterone, despite its relative inability to induce high level expression of MMTV.@@@@1@31@@oe@16-12-2010 884341308@GENIA Treebank@formal@@1@S@To investigate this further, we examined the steroid-regulated expression of an endogenous thymocyte-specific gene called GIG18.@@@@1@18@@oe@16-12-2010 884341309@GENIA Treebank@formal@@1@S@We found that GIG18 was rapidly induced to comparable levels by both AR and GR, demonstrating that AR can indeed function as a transcriptional activator in S49 cells and, moreover, that GIG18 induction may be a marker of early apoptotic events in steroid-treated cells.@@@@1@48@@oe@16-12-2010 884341310@GENIA Treebank@formal@@1@S@Taken together, these results support our conclusion that transcriptional transactivation is a necessary signaling component of S49 cell apoptosis, although an additional role for GR-mediated transrepression cannot be excluded.@@@@1@33@@oe@16-12-2010 884517201@GENIA Treebank@formal@@1@S@A model of latent adenovirus 5 infection in the guinea pig (Cavia porcellus).@@@@1@16@@oe@16-12-2010 884517202@GENIA Treebank@formal@@1@S@A model of adenovirus 5 (Ad5) infection was developed in guinea pigs to begin to study its role in the pathogenesis of peripheral lung inflammation.@@@@1@28@@oe@16-12-2010 884517203@GENIA Treebank@formal@@1@S@Forty animals were inoculated intranasally with 10(7.0) pfu of Ad5/animal, and 15 animals inoculated with sterile culture media served as controls.@@@@1@23@@oe@16-12-2010 884517204@GENIA Treebank@formal@@1@S@Viral titres were 10(4.4), 10(6.1), 10(5.2), and 10(2.9) pfu/animal, on days 1, 3, 4, and 7 after infection, respectively.@@@@1@28@@oe@16-12-2010 884517205@GENIA Treebank@formal@@1@S@In situ hybridization to viral DNA and immunocytochemistry for Ad5 E1A protein localized the virus to airway and alveolar epithelial cells.@@@@1@22@@oe@16-12-2010 884517206@GENIA Treebank@formal@@1@S@Histologic examination showed an extensive inflammatory cell infiltration around the airways, with epithelial necrosis and an alveolar exudate that caused localized alveolar collapse in the infected areas.@@@@1@29@@oe@16-12-2010 884517207@GENIA Treebank@formal@@1@S@Immunocytochemistry identified the cells in the infiltrate as cytotoxic T cells.@@@@1@12@@oe@16-12-2010 884517208@GENIA Treebank@formal@@1@S@Although all animals 20 and 47 days after infection had seroconverted to Ad5, virus was not detected in these groups either by viral plaque assay or in situ hybridization.@@@@1@31@@oe@16-12-2010 884517209@GENIA Treebank@formal@@1@S@Ad5 E1A DNA was detected by polymerase chain reaction in five of six animals 20 days after infection and in five of five animals 47 days after infection.@@@@1@29@@oe@16-12-2010 884517210@GENIA Treebank@formal@@1@S@In these same animals, E1A protein was detected 20 days after infection in two and 47 days after infection in one while persistent bronchiolitis was observed in four and three animals 20 and 47 days after infection, respectively.@@@@1@41@@oe@16-12-2010 884517211@GENIA Treebank@formal@@1@S@These results demonstrate that the guinea pig provides a useful model to study the role of Ad5 infection in chronic airway inflammation.@@@@1@23@@oe@16-12-2010 885269801@GENIA Treebank@formal@@1@S@Selenium-mediated inhibition of transcription factor NF-kappa B and HIV-1 LTR promoter activity.@@@@1@13@@oe@16-12-2010 885269802@GENIA Treebank@formal@@1@S@The eukaryotic transcription factor NF-kappa B is involved in the inducible expression of various inflammatory genes as well as in HIV-1 replication.@@@@1@23@@oe@16-12-2010 885269803@GENIA Treebank@formal@@1@S@Activation of NF-kappa B is induced by prooxidants and several stimuli eliciting oxidative stress, such as cytokines, lipopolysaccharide, UV irradiation and other mediators.@@@@1@27@@oe@16-12-2010 885269804@GENIA Treebank@formal@@1@S@Various antioxidants inhibit NF-kappa B activation in response to these stimuli.@@@@1@12@@oe@16-12-2010 885269805@GENIA Treebank@formal@@1@S@In this study, we have investigated the effects of selenium, an integral component of glutathione peroxidase (GPX), on NF-kappa B activation.@@@@1@27@@oe@16-12-2010 885269806@GENIA Treebank@formal@@1@S@In selenium-deprived Jurkat and ESb-L T lymphocytes, supplementation of selenium led to a substantial increase of GPX activity.@@@@1@20@@oe@16-12-2010 885269807@GENIA Treebank@formal@@1@S@Analysis of DNA binding revealed that NF-kappa B activation in response to TNF was significantly inhibited under these conditions.@@@@1@20@@oe@16-12-2010 885269808@GENIA Treebank@formal@@1@S@Likewise, reporter gene assays using luciferase constructs driven by the HIV-1 long terminal repeat showed a dose-dependent inhibition of NF-kappa B controlled gene expression by selenium.@@@@1@28@@oe@16-12-2010 885269809@GENIA Treebank@formal@@1@S@The effects of selenium were specific for NF-kappa B, since the activity of the transcription factor AP-1 was not suppressed.@@@@1@22@@oe@16-12-2010 885269810@GENIA Treebank@formal@@1@S@These data suggest that selenium supplementation may be used to modulate the expression of NF-kappa B target genes and HIV-1.@@@@1@21@@oe@16-12-2010 885389601@GENIA Treebank@formal@@1@S@Suppression of c-jun by antisense oligonucleotides inhibits cell adhesion but not respiratory burst during phorbol ester-induced differentiation of U937 human monoblastic cells.@@@@1@23@@oe@16-12-2010 885389602@GENIA Treebank@formal@@1@S@We studied the role of the immediate early gene c-jun in cell proliferation and phorbol 12-myristate 13-acetate (PMA)-induced differentiation in U937 human monoblastic cells, using c-jun-specific antisense (AS) phosphorothioate oligonucleotides.@@@@1@37@@oe@16-12-2010 885389603@GENIA Treebank@formal@@1@S@In selecting the most specific and potent oligonucleotide sequence, we performed extensive analyses for the binding specificity between all candidates of c-jun AS oligonucleotides and the whole sequences in GenBank database, using a computer program.@@@@1@38@@oe@16-12-2010 885389604@GENIA Treebank@formal@@1@S@Among the 20 selected oligonucleotides, two potent 15-mer AS oligonucleotides (C-JUN AS oligonucleotides) exhibited significant inhibition of cell growth in a dose-dependent manner between 2 and 10 microM.@@@@1@32@@oe@16-12-2010 885389605@GENIA Treebank@formal@@1@S@Reverse transcription-PCR and Western blot analysis demonstrated that 10 microM of C-JUN AS oligonucleotides reduced c-jun expression at both the mRNA and protein levels.@@@@1@25@@oe@16-12-2010 885389606@GENIA Treebank@formal@@1@S@More importantly, C-JUN AS oligonucleotides showed distinct effects on two markers of PMA-induced differentiation; the C-JUN AS oligonucleotides inhibited cell adhesion, whereas they did not affect another marker of differentiation, respiratory burst (measured by nitro blue tetrazolium reduction assay).@@@@1@46@@oe@16-12-2010 885389607@GENIA Treebank@formal@@1@S@These results suggest a critical role of c-jun in both cell proliferation and PMA-induced cell adhesion but not in PMA-induced respiratory burst in U937 cells.@@@@1@26@@oe@16-12-2010 885389801@GENIA Treebank@formal@@1@S@Transcriptional and posttranscriptional regulation of erythroid gene expression in anthracycline-induced differentiation of human erythroleukemic cells.@@@@1@16@@oe@16-12-2010 885389802@GENIA Treebank@formal@@1@S@Aclacinomycin (ACLA) and doxorubicin (DOX) were used at subtoxic concentrations to induce erythroid differentiation in the human leukemic cell line K562.@@@@1@26@@oe@16-12-2010 885389803@GENIA Treebank@formal@@1@S@Cell hemoglobinization was accompanied by the increased expression of genes encoding gamma-globin and porphobilinogen deaminase (PBGD), an enzyme of heme synthesis.@@@@1@25@@oe@16-12-2010 885389804@GENIA Treebank@formal@@1@S@By using run-on assays, ACLA was shown to induce an enhancement of the transcription of erythroid genes, including gamma-globin, PBGD, erythropoietin receptor, and GATA-1 transcription factor.@@@@1@32@@oe@16-12-2010 885389805@GENIA Treebank@formal@@1@S@In contrast, in DOX-treated cells, the transcription rate of these genes was unchanged in comparison with control cells.@@@@1@21@@oe@16-12-2010 885389806@GENIA Treebank@formal@@1@S@In addition, inhibition of mRNA synthesis with actinomycin D indicated that DOX induced an increased stability of PBGD and GATA-1 mRNAs, whereas ACLA did not affect the half-lives of these mRNAs.@@@@1@34@@oe@16-12-2010 885389807@GENIA Treebank@formal@@1@S@Because the increase in erythroid mRNA steady-state level in anthracycline-treated cells was inhibited by cycloheximide, this suggests that transcriptional activation in ACLA-treated cells and mRNA stabilization in DOX-treated cells were dependent on de novo protein synthesis.@@@@1@38@@oe@16-12-2010 885389808@GENIA Treebank@formal@@1@S@Finally, GATA-1 protein level was shown to be increased in ACLA-treated but not in DOX-treated cells.@@@@1@18@@oe@16-12-2010 885389809@GENIA Treebank@formal@@1@S@These two anthracyclines, although closely related in their structures, appeared to act as differentiation inducers by distinct mechanisms.@@@@1@21@@oe@16-12-2010 885389810@GENIA Treebank@formal@@1@S@Indeed, erythroid gene expression was demonstrated to be regulated transcriptionally by ACLA and mainly posttranscriptionally by DOX.@@@@1@19@@oe@16-12-2010 885815601@GENIA Treebank@formal@@1@S@Human TAFII 105 is a cell type-specific TFIID subunit related to hTAFII130.@@@@1@13@@oe@16-12-2010 885815602@GENIA Treebank@formal@@1@S@We previously characterized Drosophila and human TAF subunits that make up the core TFIID complex found in all cells.@@@@1@20@@oe@16-12-2010 885815603@GENIA Treebank@formal@@1@S@Here, we report that differentiated B cells contain a novel substoichiometric TAF of 105 kDa not found associated with TFIID isolated from other cell types.@@@@1@27@@oe@16-12-2010 885815604@GENIA Treebank@formal@@1@S@The cDNA encoding hTAFII105 reveals a highly conserved C-terminal domain shared by hTAFII130 and oTAFII110, while the N-terminal coactivator domain has diverged significantly.@@@@1@25@@oe@16-12-2010 885815605@GENIA Treebank@formal@@1@S@All cells tested express TAFII105 mRNA, but only B cells contain significant levels of protein associated with TFIID.@@@@1@20@@oe@16-12-2010 885815606@GENIA Treebank@formal@@1@S@Transient overexpression of hTAFII105 selectively squelches the transcription of some genes in B cells.@@@@1@15@@oe@16-12-2010 885815607@GENIA Treebank@formal@@1@S@These properties suggest that TAFII105 is a cell type-specific subunit of TFIID that may be responsible for mediating transcription by a subset of activators in B cells.@@@@1@28@@oe@16-12-2010 886316201@GENIA Treebank@formal@@1@S@Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene.@@@@1@25@@oe@16-12-2010 886316202@GENIA Treebank@formal@@1@S@We describe two female monozygotic (MZ) twins heterozygous for Fabry disease, an X linked disorder resulting from the deficient activity of alpha-galactosidase A.@@@@1@27@@oe@16-12-2010 886316203@GENIA Treebank@formal@@1@S@While one of the twins was clinically affected, the other was asymptomatic.@@@@1@14@@oe@16-12-2010 886316204@GENIA Treebank@formal@@1@S@Enzymatic assay of alpha-galactosidase in blood leucocytes, skin fibroblasts, Epstein-Barr virus transformed lymphoid cell lines, and hair follicles of the twins and their parents confirmed the heterozygous status of the twins and indicated that Fabry disease had occurred as a result of a de novo mutation.@@@@1@50@@oe@16-12-2010 886316205@GENIA Treebank@formal@@1@S@The son of the unaffected twin sister was shown to be hemizygous.@@@@1@13@@oe@16-12-2010 886316206@GENIA Treebank@formal@@1@S@Molecular analysis of the alpha-galactosidase A gene permitted the identification of an as yet undescribed point mutation at position 10182 of exon 5 which causes an Asp to Asn substitution at codon 231.@@@@1@34@@oe@16-12-2010 886316207@GENIA Treebank@formal@@1@S@Single strand conformation polymorphism (SSCP) analysis again showed the heterozygous status of the twins and a normal pattern in their parents.@@@@1@24@@oe@16-12-2010 886316208@GENIA Treebank@formal@@1@S@The basis for the discordant expression of this d novo mutation in the twins was investigated by studying their X inactivation status.@@@@1@23@@oe@16-12-2010 886316209@GENIA Treebank@formal@@1@S@Analysis of the inactive X specific methylation at the androgen receptor gene showed unbalanced inactivation in the twins' fibroblasts and in opposite directions.@@@@1@25@@oe@16-12-2010 886316210@GENIA Treebank@formal@@1@S@While the maternally derived X chromosome was preferentially active in the asymptomatic twin, the paternal X chromosome was active in the other, affected twin and was found in her hemizygotic nephew.@@@@1@34@@oe@16-12-2010 886316211@GENIA Treebank@formal@@1@S@These data suggest that the paternal X chromosome carries the de novo alpha-galactosidase A mutation and that uneven X inactivation is the underlying mechanism for disease expression in this novel female MZ twin pair.@@@@1@35@@oe@16-12-2010 886316212@GENIA Treebank@formal@@1@S@This is the first documented case of female twins discordant for Fabry disease.@@@@1@14@@oe@16-12-2010 886412701@GENIA Treebank@formal@@1@S@Signaling by IL-2 and related cytokines: JAKs, STATs, and relationship to immunodeficiency.@@@@1@16@@oe@16-12-2010 886412702@GENIA Treebank@formal@@1@S@Cytokines that bind to the interleukin-2 (IL-2) receptor common gamma chain (gamma c), including IL-2, IL-4, IL-7, IL-9, and IL-15, are important for the growth and differentiation of T and B lymphocytes, natural killer cells, macrophages, and monoctyes.@@@@1@52@@oe@16-12-2010 886412703@GENIA Treebank@formal@@1@S@These cytokines have overlapping biological effects that in part result from the use of the shared receptor subunit gamma c.@@@@1@21@@oe@16-12-2010 886412704@GENIA Treebank@formal@@1@S@Recently it has become clear that these cytokines activate a number of important intracellular signaling molecules, including the Janus kinases JAK1 and JAK3 and members of the transcription factor family of signal transducers and activators of transcription (STATs).@@@@1@42@@oe@16-12-2010 886412705@GENIA Treebank@formal@@1@S@The discovery of these signaling pathways has led to important new insights into their role in lymphocyte maturation, as it has emerged that mutations in the genes encoding both gamma c and JAK3 result in similar forms of severe combined immunodeficiency (SCID).@@@@1@46@@oe@16-12-2010 886412706@GENIA Treebank@formal@@1@S@In this review we examine the structure and function of cytokine receptors and the signaling pathways involved in their regulation of gene expression.@@@@1@24@@oe@16-12-2010 886412707@GENIA Treebank@formal@@1@S@Furthermore, we discuss recent advances that have led to a better understanding of how cytokines elicit intracellular responses, as well as their role in normal lymphoid development.@@@@1@30@@oe@16-12-2010 886806901@GENIA Treebank@formal@@1@S@Cloning and characterization of the murine B-cell specific transcriptional coactivator Bob1.@@@@1@12@@oe@16-12-2010 886806902@GENIA Treebank@formal@@1@S@From a murine B-cell cDNA-library we have cloned a cDNA encoding the murine B-cell specific coactivator mBob1.@@@@1@18@@oe@16-12-2010 886806903@GENIA Treebank@formal@@1@S@The protein is the murine homologue to the recently described human coactivator Bob1 (hBob1), also referred to as OBF-1 or OCA-B.@@@@1@25@@oe@16-12-2010 886806904@GENIA Treebank@formal@@1@S@We have also characterized the genomic mBob1 clone.@@@@1@9@@oe@16-12-2010 886806905@GENIA Treebank@formal@@1@S@Analysis of its intron-exon structure has allowed identification of a C-terminal splice variant.@@@@1@14@@oe@16-12-2010 886806906@GENIA Treebank@formal@@1@S@mBob1 is B-cell restricted, and is found in all B-cell lines representing different stages of B-cell differentiation.@@@@1@19@@oe@16-12-2010 886806907@GENIA Treebank@formal@@1@S@mBob1 interacts with the octamer transcription factors Oct-1 and Oct-2 and stimulates transcription mediated by these factors.@@@@1@18@@oe@16-12-2010 887105601@GENIA Treebank@formal@@1@S@Eosinophil priming by cytokines: from cellular signal to in vivo modulation.@@@@1@13@@oe@16-12-2010 887105602@GENIA Treebank@formal@@1@S@Eosinophils play an important role in the effector phase of allergic inflammation.@@@@1@13@@oe@16-12-2010 887105603@GENIA Treebank@formal@@1@S@This review will focus on the conversion of the unprimed eosinophil phenotype in the peripheral blood of normal individuals to the primed phenotype found in the peripheral blood and tissues of allergic patients, a phenomenon called priming.@@@@1@39@@oe@16-12-2010 887105604@GENIA Treebank@formal@@1@S@Recent data on the signals initiated after cytokine receptor activation on eosinophils will be reviewed.@@@@1@16@@oe@16-12-2010 887106101@GENIA Treebank@formal@@1@S@Molecular mechanisms of steroid action: a novel type of cross-talk between glucocorticoids and NF-kappa B transcription factors.@@@@1@19@@oe@16-12-2010 887106102@GENIA Treebank@formal@@1@S@Despite the widespread use of glucocorticoids in the treatment of diseases characterized by inflammation, the molecular mechanism(s) by which these hormones exert this beneficial effect in patients with asthma remains to be elucidated.@@@@1@38@@oe@16-12-2010 887106103@GENIA Treebank@formal@@1@S@Therefore, we have studied the transcriptional regulation of intercellular adhesion molecule-1 (ICAM-1) as adhesion molecules are likely to play a causal role in inflammation in promoting cell-cell and cell-matrix interactions.@@@@1@34@@oe@16-12-2010 887106104@GENIA Treebank@formal@@1@S@We observed that in a monocytic (U937) and a bronchial epithelial (H292) cell-line dexamethasone strongly suppressed basal and induced ICAM-1 expression.@@@@1@26@@oe@16-12-2010 887106105@GENIA Treebank@formal@@1@S@Subsequent analysis of the human ICAM-1 promoter has revealed that both 12-O-tetradecanoylphorbol 13-acetate (TPA) and tumour necrosis factor-alpha (TNF-alpha) upregulate ICAM-1 expression through the presence of a nuclear factor (NF-kappa B) target sequence (TGGAAATTCC).@@@@1@43@@oe@16-12-2010 887106106@GENIA Treebank@formal@@1@S@No glucocorticoid recognition sequences are present in this promoter region and dexamethasone is still able to repress transcription when the multimerized NF-kappa B sequence is transactivated by TNF-alpha upon transfection in 293 cells.@@@@1@34@@oe@16-12-2010 887106107@GENIA Treebank@formal@@1@S@We propose that direct interaction between the glucocorticoid receptor and nuclear factor-kappa B factors is at least a partial explanation for the effects of this hormone in inflammatory diseases.@@@@1@30@@oe@16-12-2010 887160801@GENIA Treebank@formal@@1@S@The suppression of T cell function and NF(kappa)B expression by serine protease inhibitors is blocked by N-acetylcysteine.@@@@1@18@@oe@16-12-2010 887160802@GENIA Treebank@formal@@1@S@Direct evidence that N-acetylcysteine (NAC) enhances the immune response of peripheral blood T cells at the level of NF(kappa)B is presented.@@@@1@24@@oe@16-12-2010 887160803@GENIA Treebank@formal@@1@S@In addition, NAC blocks the suppression of T cell mitogenesis and cytokine production by protease inhibitors such as N-tosylphenylalanine chloromethyl ketone (TPCK).@@@@1@26@@oe@16-12-2010 887160804@GENIA Treebank@formal@@1@S@The proliferative responses of purified CD4+ or CD8+ T cells are suppressed more strongly by TPCK when anti-CD28 rather than the phorbol ester PMA is used as the mitogenic coactivator.@@@@1@31@@oe@16-12-2010 887160805@GENIA Treebank@formal@@1@S@Cytokine (IL-2, IL-6, INF-gamma) production is inhibited 95-100% by concentrations of TPCK that totally suppress the mitogenesis of CD4+ or CD8+ cells.@@@@1@28@@oe@16-12-2010 887160806@GENIA Treebank@formal@@1@S@Using electrophoretic mobility shift assays, we find that TPCK virtually abolishes (to less than 1%) the levels of NF(kappa)B (but not Oct-1) found in nuclear and whole cell extracts of activated T cells.@@@@1@40@@oe@16-12-2010 887160807@GENIA Treebank@formal@@1@S@Strikingly, the immunosuppressive effects of TPCK are blocked when T cells are pretreated for 15 min with 5 mM NAC.@@@@1@22@@oe@16-12-2010 887160808@GENIA Treebank@formal@@1@S@NAC not only blocks the effect of TPCK but enhances mitogenesis and cytokine production (>2.5-fold in some cases) upon activation of unsuppressed T cells.@@@@1@28@@oe@16-12-2010 887160809@GENIA Treebank@formal@@1@S@Our data support the notion that NF(kappa)B and I(kappa)B proteases play obligate roles in T cell activation and mitogenesis, roles that are enhanced significantly by NAC.@@@@1@28@@oe@16-12-2010 887161701@GENIA Treebank@formal@@1@S@IL-12-induced activation of NK and T cells occurs in the absence of immediate-early activation gene expression.@@@@1@17@@oe@16-12-2010 887161702@GENIA Treebank@formal@@1@S@The responses of lymphocytes to IL-2 and IL-12, involving proliferation, differentiation, and cytokine production, are only partially overlapping, and may depend on induced differential expression of specific sets of genes.@@@@1@36@@oe@16-12-2010 887161703@GENIA Treebank@formal@@1@S@Using reverse-transcription PCR differential display, we isolated an mRNA species expressed in IL-2- but not IL-12-stimulated NK cells.@@@@1@20@@oe@16-12-2010 887161704@GENIA Treebank@formal@@1@S@This was identified as the mRNA encoding the transcription factor egr-1, which is expressed with fast kinetics in T and NK cells upon IL-2, but not IL-12, stimulation.@@@@1@32@@oe@16-12-2010 887161705@GENIA Treebank@formal@@1@S@Analysis of the accumulation of mRNA-encoding members of the AP-1 transcription factor family demonstrated that c-fos and junB are also expressed upon stimulation of NK and T cells with IL-2, but not IL-12, whereas expression of c-jun and junD is not modified by either cytokine.@@@@1@48@@oe@16-12-2010 887161706@GENIA Treebank@formal@@1@S@Accordingly, increased AP-1 DNA-binding activity and AP-1-dependent transcriptional activity were detected exclusively in IL-2-stimulated cells.@@@@1@17@@oe@16-12-2010 887161707@GENIA Treebank@formal@@1@S@Analysis of the expression of genes reported to regulate cytokine-induced proliferation demonstrated that both IL-2 and IL-12 induce c-myc mRNA accumulation in NK and T cells, whereas only IL-2 induces bcl-2 expression.@@@@1@34@@oe@16-12-2010 887161708@GENIA Treebank@formal@@1@S@Our data provide the first demonstration that IL-12-mediated activation of T and NK cells does not involve expression of members of the immediate-early activation genes family (egr-1, c-fos, and junB), AP-1 transcriptional activity, or bcl-2 expression.@@@@1@43@@oe@16-12-2010 887161709@GENIA Treebank@formal@@1@S@This indicates that functional differences observed in IL-2- and IL-12-stimulated cells may depend, at least in part, on differential gene regulation.@@@@1@24@@oe@16-12-2010 887162301@GENIA Treebank@formal@@1@S@Induction of activator protein (AP)-1 and nuclear factor-kappaB by CD28 stimulation involves both phosphatidylinositol 3-kinase and acidic sphingomyelinase signals.@@@@1@23@@oe@16-12-2010 887162302@GENIA Treebank@formal@@1@S@A major obstacle in understanding the signaling events that follow CD28 receptor ligation arises from the fact that CD28 acts as a costimulus to TCR engagement, making it difficult to assess the relative contribution of CD28 signals as distinct from those of the TCR.@@@@1@46@@oe@16-12-2010 887162303@GENIA Treebank@formal@@1@S@To overcome this problem, we have exploited the observation that activated human T cell blasts can be stimulated via the CD28 surface molecule in the absence of antigenic challenge; thus, we have been able to observe the response of normal T cells to CD28 activation in isolation.@@@@1@51@@oe@16-12-2010 887162304@GENIA Treebank@formal@@1@S@Using this system, we observed that CD28 stimulation by B7-transfected CHO cells induced a proliferative response in T cells that was not accompanied by measurable IL-2 production.@@@@1@29@@oe@16-12-2010 887162305@GENIA Treebank@formal@@1@S@However, subsequent analysis of transcription factor generation revealed that B7 stimulation induced both activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) complexes, but not NF-AT.@@@@1@31@@oe@16-12-2010 887162306@GENIA Treebank@formal@@1@S@In contrast, engagement of the TCR by class II MHC/superantigen, either with or without CD28 ligation, resulted in the induction of NF-AT, AP-1, and NF-kappaB as well as IL-2 production.@@@@1@36@@oe@16-12-2010 887162307@GENIA Treebank@formal@@1@S@Using selective inhibitors, we investigated the signaling pathways involved in the CD28-mediated induction of AP-1 and NF-kappaB.@@@@1@19@@oe@16-12-2010 887162308@GENIA Treebank@formal@@1@S@This revealed that NF-kappaB generation was sensitive to chloroquine, an inhibitor of acidic sphingomyelinase, but not to the phosphatidylinositol 3-kinase inhibitor, wortmannin.@@@@1@26@@oe@16-12-2010 887162309@GENIA Treebank@formal@@1@S@In contrast, AP-1 generation was inhibited by wortmannin and was also variably sensitive to chloroquine.@@@@1@17@@oe@16-12-2010 887162310@GENIA Treebank@formal@@1@S@These data suggest that in activated normal T cells, CD28-derived signals can stimulate proliferation at least in part via NF-kappaB and AP-1 generation, and that this response uses both acidic sphingomyelinase and phosphatidylinositol 3-kinase-linked pathways.@@@@1@38@@oe@16-12-2010 887164901@GENIA Treebank@formal@@1@S@A critical role of Sp1- and Ets-related transcription factors in maintaining CTL-specific expression of the mouse perforin gene.@@@@1@19@@oe@16-12-2010 887164902@GENIA Treebank@formal@@1@S@This study was designed to determine the potential cis-elements involved in transcriptional regulation of the mouse perforin gene.@@@@1@19@@oe@16-12-2010 887164903@GENIA Treebank@formal@@1@S@DNase I hypersensitive site (DHS) mapping revealed that the perforin locus contained six DHS within 7.0 kb of the 5' upstream sequence (-7.0 kb) and two DHS in intron 2.@@@@1@35@@oe@16-12-2010 887164904@GENIA Treebank@formal@@1@S@The six 5' upstream and one intronic DHS were detected in only perforin-expressing lymphocytes.@@@@1@15@@oe@16-12-2010 887164905@GENIA Treebank@formal@@1@S@Chloramphenicol acetyltransferase (CAT) activities directed by 5' upstream promoter were detected preferentially in perforin-expressing cell lines.@@@@1@19@@oe@16-12-2010 887164906@GENIA Treebank@formal@@1@S@A construct termed PFP5a containing -795 bp exhibited the highest CAT activity, and PFP9a20 containing only -73 bp also produced significantly high CAT activity in CTLL-R8 cells.@@@@1@29@@oe@16-12-2010 887164907@GENIA Treebank@formal@@1@S@The proximal region in PFP9a20 contained two potential Sp1 binding sites (GC box and GT box) and one Ets binding site (EBS).@@@@1@27@@oe@16-12-2010 887164908@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assay showed that each of the cis-elements bound specific protein factors.@@@@1@15@@oe@16-12-2010 887164909@GENIA Treebank@formal@@1@S@When single-point mutation was introduced to each GC box, EBS, and GT box in PFP9a20, at least 3-fold less CAT activity was observed in CTLL-R8 cells.@@@@1@30@@oe@16-12-2010 887164910@GENIA Treebank@formal@@1@S@To confirm the importance of the three cis-acting elements in the perforin gene expression, point mutation was introduced again to each proximal GC box, EBS, and GT box of PFP5a.@@@@1@34@@oe@16-12-2010 887164911@GENIA Treebank@formal@@1@S@The point mutations resulted in a 2.5- to 3-fold reduction of CAT activity.@@@@1@14@@oe@16-12-2010 887164912@GENIA Treebank@formal@@1@S@The results suggest that a combination of the three proximal cis-acting elements may constitute a minimal region responsible for CTL-specific expression of perforin.@@@@1@24@@oe@16-12-2010 887187701@GENIA Treebank@formal@@1@S@Stimulation of human lymphocyte proliferation and CD40 antigen expression by phosphorothioate oligonucleotides complementary to hepatitis B virus genome.@@@@1@19@@oe@16-12-2010 887187702@GENIA Treebank@formal@@1@S@We have studied the proliferation and CD40 antigen expression of lymphocytes, and the cytotoxicity to monocytes, of antisense phosphorothioate oligodeoxynucleotides complementary to the SP II promoter of HBV mRNA (sequence I) and the X gene (sequence II) in patients with chronic hepatitis B.@@@@1@50@@oe@16-12-2010 887187703@GENIA Treebank@formal@@1@S@The oligo sequence I stimulated proliferation of both T and, to a lesser extent, B cells.@@@@1@19@@oe@16-12-2010 887187704@GENIA Treebank@formal@@1@S@The percentage of cells expressing CD40 in T and B cell co-cultures increased from 4.2% to 13.8% after oligo stimulation in patients, while it increased form 4.7% to 48.6% in healthy controls.@@@@1@38@@oe@16-12-2010 887187705@GENIA Treebank@formal@@1@S@The sense sequence (sequence III) of the X gene also enhanced the expression of CD40 antigen in patients with hepatitis B.@@@@1@24@@oe@16-12-2010 887187706@GENIA Treebank@formal@@1@S@The proportion of CD40 cells (26%) in a resting B-cell preparation from hepatitis B patients decreased to zero after a 5-day culture with sequence I, but IgG levels in the culture supernatant increased.@@@@1@38@@oe@16-12-2010 887187707@GENIA Treebank@formal@@1@S@The cytotoxic properties of monocytes were not influenced by the oligos.@@@@1@12@@oe@16-12-2010 887187708@GENIA Treebank@formal@@1@S@These findings indicate that antisense oligos against hepatitis B virus (HBV) have mitogenic effects on the proliferation of human lymphocytes in a non-specific manner and may activate T cells to express CD40 antigen.@@@@1@36@@oe@16-12-2010 887260601@GENIA Treebank@formal@@1@S@Soluble factors secreted by activated T-lymphocytes modulate the transcription of the immunosuppressive cytokine TGF-beta 2 in glial cells.@@@@1@19@@oe@16-12-2010 887260602@GENIA Treebank@formal@@1@S@Coordination of the immune response to injury or disease in the brain is postulated to involve bi-directional discourse between the immune system and the central nervous system.@@@@1@28@@oe@16-12-2010 887260603@GENIA Treebank@formal@@1@S@This cross communication involves soluble mediators, including various growth factors, cytokines, and neuropeptides.@@@@1@17@@oe@16-12-2010 887260604@GENIA Treebank@formal@@1@S@In this report, we demonstrate that the supernatant from activated T-lymphocytes is able to induce the transcription of a potent cytokine, TGF-beta 2 in glial cells.@@@@1@29@@oe@16-12-2010 887260605@GENIA Treebank@formal@@1@S@The activating stimulus invokes signaling mechanisms distinct from known kinase or protease pathways.@@@@1@14@@oe@16-12-2010 887260606@GENIA Treebank@formal@@1@S@Activation of TGF-beta 2 transcription correlates with the loss of binding activity for an 80 kDA glial labile repressor protein, GLRP, to a responsive region within the TFG-beta 2 promoter.@@@@1@33@@oe@16-12-2010 887260607@GENIA Treebank@formal@@1@S@Although GLRP shares some characteristics with the inducible transcription factor AP-1, it appears to be distinct from known AP-1 family members.@@@@1@23@@oe@16-12-2010 887260608@GENIA Treebank@formal@@1@S@These data along with previous observations demonstrating the potent immunosuppressive activity of TGF-beta 2, support a model for a feedback mechanism between the activated T-lymphocytes and astrocytes via TGF-beta 2 to regulate the immune response.@@@@1@37@@oe@16-12-2010 887418401@GENIA Treebank@formal@@1@S@Dual action of retinoic acid on human embryonic/fetal hematopoiesis: blockade of primitive progenitor proliferation and shift from multipotent/erythroid/monocytic to granulocytic differentiation program.@@@@1@24@@oe@16-12-2010 887418402@GENIA Treebank@formal@@1@S@In preliminary studies, we have analyzed the hematopoietic growth factor (HGF) requirement of hematopoietic progenitor cells (HPCs) purified from embryonic-fetal liver (FL) and grown in fetal calf serum-supplemented (FCS+) clonogenic culture.@@@@1@41@@oe@16-12-2010 887418403@GENIA Treebank@formal@@1@S@The key role of erythropoietin (Epo) for colony formation by early erythroid progenitors (burst-forming units-erythroid [BFU-E]) has been confirmed.@@@@1@26@@oe@16-12-2010 887418404@GENIA Treebank@formal@@1@S@Furthermore, in the absence of exogenous HGFs, FL monocytic progenitors (colony-forming unit monocyte [CFU-M]) generate large colonies exclusively composed of monocytes-macrophages; these colonies are absent in FCS- clonogenic culture.@@@@1@37@@oe@16-12-2010 887418405@GENIA Treebank@formal@@1@S@On this basis, we have investigated the role of all-trans retinoic acid (ATRA) and its isomer 9-cis RA in FL hematopoiesis.@@@@1@25@@oe@16-12-2010 887418406@GENIA Treebank@formal@@1@S@Both compounds modulate the growth of purified FL HPCs, which show a dose-dependent shift from mixed/erythroid/monocytic to granulocytic colony formation.@@@@1@22@@oe@16-12-2010 887418407@GENIA Treebank@formal@@1@S@Studies on unicellular and paired daughter cell culture unequivocally indicate that the shift is mediated by modulation of the HPC differentiation program to the granulopoietic pathway (rather than RA-induced down-modulation of multipotent /erythroid/monocytic HPC growth coupled with recruitment of granulocytic HPCs).@@@@1@43@@oe@16-12-2010 887418408@GENIA Treebank@formal@@1@S@ATRA and 9-cis RA also exert their effect on the proliferation of primitive HPCs (high-proliferative potential colony-forming cells [HPP-CFCs]) and putative hematopoietic stem cells (HSCs; assayed in Dexter-type long-term culture).@@@@1@38@@oe@16-12-2010 887418409@GENIA Treebank@formal@@1@S@High concentrations of either compound (1) drastically reduced the number of primary HPP-CFC colonies and totally abolished their recloning capacity and (2) inhibited HSC proliferation.@@@@1@30@@oe@16-12-2010 887418410@GENIA Treebank@formal@@1@S@It is crucial that these results mirror recent observations indicating that murine adult HPCs transduced with dominant negative ATRA receptor (RAR) gene are immortalized and show a selective blockade of granulocytic differentiation.@@@@1@35@@oe@16-12-2010 887418411@GENIA Treebank@formal@@1@S@Altogether, these results suggest that ATRA/9-cis RA may play a key role in FL hematopoiesis via a dual effect hypothetically mediated by interaction with the RAR/RXR heterodimer, ie, inhibition of HSC/ primitive HPC proliferation and induction of CFU-GEMM/ BFU-E/CFU-M shift from the multipotent/erythroid/monocytic to the granulocytic-neutrophilic differentiation program.@@@@1@52@@oe@16-12-2010 887594201@GENIA Treebank@formal@@1@S@Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95.@@@@1@15@@oe@16-12-2010 887594202@GENIA Treebank@formal@@1@S@Tumor necrosis factor receptor-1 (TNFR-1) and CD95 (also called Fas or APO-1) are cytokine receptors that engage the apoptosis pathway through a region of intracellular homology, designated the "death domain."@@@@1@38@@oe@16-12-2010 887594203@GENIA Treebank@formal@@1@S@Another death domain-containing member of the TNFR family, death receptor 3 (DR3), was identified and was shown to induce both apoptosis and activation of nuclear factor kappaB.@@@@1@32@@oe@16-12-2010 887594204@GENIA Treebank@formal@@1@S@Expression of DR3 appears to be restricted to tissues enriched in lymphocytes.@@@@1@13@@oe@16-12-2010 887594205@GENIA Treebank@formal@@1@S@DR3 signal transduction is mediated by a complex of intracellular signaling molecules including TRADD, TRAF2, FADD, and FLICE.@@@@1@22@@oe@16-12-2010 887594206@GENIA Treebank@formal@@1@S@Thus, DR3 likely plays a role in regulating lymphocyte homeostasis.@@@@1@12@@oe@16-12-2010 887710401@GENIA Treebank@formal@@1@S@Vitamin D3- and retinoic acid-induced monocytic differentiation: interactions between the endogenous vitamin D3 receptor, retinoic acid receptors, and retinoid X receptors in U-937 cells.@@@@1@28@@oe@16-12-2010 887710402@GENIA Treebank@formal@@1@S@Retinoic acid (RA) and 1,25 alpha-dihydroxycholecalciferol (VitD3) are potent regulators of hematopoletic differentiation.@@@@1@18@@oe@16-12-2010 887710403@GENIA Treebank@formal@@1@S@Yet, little is known as to how the RA and VitD3 receptor network operates in hematopoietic cells, and whether receptor interactions can explain the interplay between the RA- and VitD3-signaling pathways during differentiation.@@@@1@36@@oe@16-12-2010 887710404@GENIA Treebank@formal@@1@S@Therefore, we analyzed the expression, DNA binding, and transcriptional activity of the endogenous RA and VitD3 receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), and VitD3 receptor (VDR)] in the U-937 cell line, in which RA and VitD3 induce distinct monocytic differentiation pathways.@@@@1@59@@oe@16-12-2010 887710405@GENIA Treebank@formal@@1@S@VitD3 induction resulted in the formation of VDR/RXR DNA-binding complexes on both VitD3 response elements and RA response elements (RAREs).@@@@1@23@@oe@16-12-2010 887710406@GENIA Treebank@formal@@1@S@However, transcriptional activation was only observed from a VitD3 response element-driven reporter construct.@@@@1@15@@oe@16-12-2010 887710407@GENIA Treebank@formal@@1@S@Several DNA-binding complexes were detected on RAREs in undifferentiated cells.@@@@1@11@@oe@16-12-2010 887710408@GENIA Treebank@formal@@1@S@Stimulation by RA resulted in increased RAR beta/RXR DNA binding, activated RARE-dependent transcription, and increased expression of RAR-beta.@@@@1@21@@oe@16-12-2010 887710409@GENIA Treebank@formal@@1@S@Concomitant stimulation by VitD3 inhibited the RA-stimulated formation of RAR beta/RXR heterodimers, favoring VDR/RXR binding to the RARE.@@@@1@20@@oe@16-12-2010 887710410@GENIA Treebank@formal@@1@S@Also, VitD3 inhibited the expression of CD23 and CD49f, characteristic markers of retinoid-induced U-937 cell differentiation.@@@@1@19@@oe@16-12-2010 887710411@GENIA Treebank@formal@@1@S@In contrast, neither the RA-stimulated, RARE-mediated transcription nor the induced RAR-beta expression was suppressed by VitD3, suggesting that VitD3 selectively inhibited the retinoid-induced differentiation program but not the RARE-mediated signal.@@@@1@34@@oe@16-12-2010 887710412@GENIA Treebank@formal@@1@S@These results demonstrate a complex role for VitD3 in modifying the retinoid differentiation pathway and may have implications for differentiation-inducing therapy of hematopoietic tumors.@@@@1@25@@oe@16-12-2010 887772501@GENIA Treebank@formal@@1@S@Regulation of interferon-gamma gene expression.@@@@1@6@@oe@16-12-2010 887772502@GENIA Treebank@formal@@1@S@Interferon-gamma ( IFN-gamma ), also known as type II interferon, is an important immunoregulatory gene that has multiple effects on the development, maturation, and function of the immune system.@@@@1@34@@oe@16-12-2010 887772503@GENIA Treebank@formal@@1@S@IFN-gamma mRNA and protein are expressed predominantly by T cells and large granular lymphocytes.@@@@1@15@@oe@16-12-2010 887772504@GENIA Treebank@formal@@1@S@The IFN-gamma mRNA is induced/inhibited in these cell types by a wide variety of extracellular signals, thus implicating a number of diverse, yet convergent signal transduction pathways in its transcriptional control.@@@@1@34@@oe@16-12-2010 887772505@GENIA Treebank@formal@@1@S@In this review, I describe how DNA methylation and specific DNA binding proteins may regulate transcription of the IFN-gamma gene in response to extracellular signals.@@@@1@27@@oe@16-12-2010 887852401@GENIA Treebank@formal@@1@S@Inorganic lead activates NF-kappa B in primary human CD4+ T lymphocytes.@@@@1@12@@oe@16-12-2010 887852402@GENIA Treebank@formal@@1@S@Inorganic lead (Pb) is a ubiquitous environmental contaminant that produces a variety of effects on humoral and cell mediated immune responses.@@@@1@24@@oe@16-12-2010 887852403@GENIA Treebank@formal@@1@S@The underlying molecular mechanism for Pb's complex effects on the immune system remain obscure.@@@@1@16@@oe@16-12-2010 887852404@GENIA Treebank@formal@@1@S@Many of Pb's effects on the immune system could be explained through activation of the transcription factor, NF-kappa B.@@@@1@22@@oe@16-12-2010 887852405@GENIA Treebank@formal@@1@S@NF-kappa B is critical for T lymphocyte function and is a strong inducer of HIV-LTR activation.@@@@1@17@@oe@16-12-2010 887852406@GENIA Treebank@formal@@1@S@We demonstrate that Pb at physiologically relevant concentrations activates NF-kappa B in primary human CD4+ T lymphocytes.@@@@1@18@@oe@16-12-2010 887852407@GENIA Treebank@formal@@1@S@Pb-induced activation of NF-kappa B is blocked by antibodies for p65 and p50 subunits but not cRel, indicating that the p65:p50 heterodimer (NF-kappa B) is involved.@@@@1@30@@oe@16-12-2010 887852408@GENIA Treebank@formal@@1@S@Functional activation of gene expression by Pb was confirmed using primary CD4+ T cells transfected with an NF-kappa B dependent reporter gene construct.@@@@1@24@@oe@16-12-2010 887852409@GENIA Treebank@formal@@1@S@Pb did not activate NF-kappa B in 4 different T cell lines, suggesting that lymphoid cell lines may not be reliable surrogates for the study of transcriptional activation in human T cells.@@@@1@34@@oe@16-12-2010 887852410@GENIA Treebank@formal@@1@S@These data suggest that NF-kappa B may be an important molecular mediator of Pb-induced immunotoxicity.@@@@1@16@@oe@16-12-2010 888768701@GENIA Treebank@formal@@1@S@Calcium-dependent immediate-early gene induction in lymphocytes is negatively regulated by p21Ha-ras.@@@@1@12@@oe@16-12-2010 888768702@GENIA Treebank@formal@@1@S@The induction of immediate-early (IE) response genes, such as egr-1, c-fos, and c-jun, occurs rapidly after the activation of T lymphocytes.@@@@1@28@@oe@16-12-2010 888768703@GENIA Treebank@formal@@1@S@The process of activation involves calcium mobilization, activation of protein kinase C (PKC), and phosphorylation of tyrosine kinases.@@@@1@23@@oe@16-12-2010 888768704@GENIA Treebank@formal@@1@S@p21(ras), a guanine nucleotide binding factor, mediates T-cell signal transduction through PKC-dependent and PKC-independent pathways.@@@@1@18@@oe@16-12-2010 888768705@GENIA Treebank@formal@@1@S@The involvement of p21(ras) in the regulation of calcium-dependent signals has been suggested through analysis of its role in the activation of NF-AT.@@@@1@24@@oe@16-12-2010 888768706@GENIA Treebank@formal@@1@S@We have investigated the inductions of the IE genes in response to calcium signals in Jurkat cells (in the presence of activated p21(ras)) and their correlated consequences.@@@@1@30@@oe@16-12-2010 888768707@GENIA Treebank@formal@@1@S@The expression of activated p21(ras) negatively regulated the induction of IE genes by calcium ionophore.@@@@1@16@@oe@16-12-2010 888768708@GENIA Treebank@formal@@1@S@This inhibition of calcium-activated IE gene induction was reversed by treatment with cyclosporin A, suggesting the involvement of calcineurin in this regulation.@@@@1@24@@oe@16-12-2010 888768709@GENIA Treebank@formal@@1@S@A later result of inhibition of this activation pathway by p21(ras) was down-regulation of the activity of the transcription factor AP-1 and subsequent coordinate reductions in IL-2 gene expression and protein production.@@@@1@33@@oe@16-12-2010 888768710@GENIA Treebank@formal@@1@S@These results suggest that p2l(ras) is an essential mediator in generating not only positive but also negative modulatory mechanisms controlling the competence of T cells in response to inductive stimulations.@@@@1@31@@oe@16-12-2010 889019601@GENIA Treebank@formal@@1@S@CD14-mediated signal pathway of Porphyromonas gingivalis lipopolysaccharide in human gingival fibroblasts.@@@@1@12@@oe@16-12-2010 889019602@GENIA Treebank@formal@@1@S@Lipopolysaccharide (LPS) induces expression of inflammatory cytokines in monocytes/macrophages via CD14, one of the LPS receptors, which is expressed predominantly in these cells.@@@@1@28@@oe@16-12-2010 889019603@GENIA Treebank@formal@@1@S@It has been demonstrated that Porphyromonas gingivalis LPS (P-LPS) also is able to induce inflammatory cytokines in human gingival fibroblasts.@@@@1@23@@oe@16-12-2010 889019604@GENIA Treebank@formal@@1@S@Therefore, it is important to determine whether CD14 is expressed in gingival fibroblasts and to define the P-LPS-mediated signal-transducing mechanism in the cells.@@@@1@25@@oe@16-12-2010 889019605@GENIA Treebank@formal@@1@S@In this study, we observed unexpectedly by immunohistochemical, Western blotting (immunoblotting), and Northern (RNA) blotting assays that CD14 is expressed at high density in human gingival fibroblasts.@@@@1@35@@oe@16-12-2010 889019606@GENIA Treebank@formal@@1@S@P-LPS-induced expression of the monocyte chemoattractant protein 1 (MCP-1) gene in the cells was inhibited markedly by treatment with anti-human CD14 antibody and was completely inhibited by herbimycin A, a potent inhibitor of tyrosine kinase.@@@@1@39@@oe@16-12-2010 889019607@GENIA Treebank@formal@@1@S@The inhibitor also dramatically inhibited monocyte chemotactic activity of and MCP-1 production by the cells.@@@@1@16@@oe@16-12-2010 889019608@GENIA Treebank@formal@@1@S@Furthermore, P-LPS-induced expression of the MCP-1 gene in the cells also was blocked by inhibitors of two transcription factors, i.e., curcumin, an inhibitor of AP-1, and pyrolidine dithiocarbamate, an inhibitor of NF-kappaB.@@@@1@39@@oe@16-12-2010 889019609@GENIA Treebank@formal@@1@S@Both inhibitors inhibited monocyte chemotactic activity in the culture supernatant of P-LPS-treated cells.@@@@1@14@@oe@16-12-2010 889019610@GENIA Treebank@formal@@1@S@Gel shift mobility assay showed stimulation of the AP-1 and NF-kappaB contents in P-LPS-treated cells.@@@@1@16@@oe@16-12-2010 889019611@GENIA Treebank@formal@@1@S@This study is the first to demonstrate the expression of CD14 in human gingival fibroblasts and to show that the signal-transducing pathway of P-LPS in the cells is mediated by CD14.@@@@1@32@@oe@16-12-2010 889204201@GENIA Treebank@formal@@1@S@Detection of intracellular signal transduction molecules in PBMC from rhesus macaques and sooty mangabeys.@@@@1@15@@oe@16-12-2010 889204202@GENIA Treebank@formal@@1@S@One of the manifestations of human HIV-1 and nonhuman primate SIV infection that lead to disease is reasoned to be secondary to generalized T-cell dysfunction.@@@@1@26@@oe@16-12-2010 889204203@GENIA Treebank@formal@@1@S@The molecular mechanisms associated with the T-cell dysfunction remain to be elucidated.@@@@1@13@@oe@16-12-2010 889204204@GENIA Treebank@formal@@1@S@To address this issue, we sought to utilize the nonhuman primate model to study intracellular signaling events in cells from disease-susceptible rhesus macaques and disease-resistant sooty mangabeys.@@@@1@29@@oe@16-12-2010 889204205@GENIA Treebank@formal@@1@S@Because relatively little is known about these events in nonhuman primates, our laboratory defined optimal conditions, reagents, and assays for the study of signal transduction events in cells from nonhuman primates.@@@@1@35@@oe@16-12-2010 889204206@GENIA Treebank@formal@@1@S@The protein phosphorylation patterns in the two monkeys exhibited quantitative, qualitative, and kinetic differences.@@@@1@17@@oe@16-12-2010 889204207@GENIA Treebank@formal@@1@S@Antibodies to Stat6 detected a unique band in macaque cell lysates.@@@@1@12@@oe@16-12-2010 889204208@GENIA Treebank@formal@@1@S@This band is markedly decreased human cell lysates and never seen in mangabey cell lysates.@@@@1@16@@oe@16-12-2010 889204209@GENIA Treebank@formal@@1@S@Detection of various other intracellular signaling proteins is also described.@@@@1@11@@oe@16-12-2010 889260401@GENIA Treebank@formal@@1@S@Tyrosines 113, 128, and 145 of SLP-76 are required for optimal augmentation of NFAT promoter activity.@@@@1@19@@oe@16-12-2010 889260402@GENIA Treebank@formal@@1@S@SLP-76 (SH2 domain leukocyte protein of 76 kDa) is a recently identified substrate of the TCR-stimulated protein tyrosine kinases that functions in the signal transduction cascade linking the TCR with IL-2 gene expression.@@@@1@36@@oe@16-12-2010 889260403@GENIA Treebank@formal@@1@S@In this report, we demonstrate that engagement of the TCR results in tyrosine phosphorylation of SLP-76 in its amino-terminal acidic region.@@@@1@23@@oe@16-12-2010 889260404@GENIA Treebank@formal@@1@S@Two tyrosines (Y113 and Y128) fall within an identical five amino-acid motif and are shown to be phosphorylated upon TCR ligation.@@@@1@24@@oe@16-12-2010 889260405@GENIA Treebank@formal@@1@S@Although mutation of either Y113 and Y128 has a minimal effect on SLP-76 function, mutation of both residues decreases significantly the ability of SLP-76 to promote T cell activation.@@@@1@31@@oe@16-12-2010 889260406@GENIA Treebank@formal@@1@S@A third tyrosine within the amino-terminal region (Y145) appears to be the most important for optimal SLP-76 function, as altering it alone to phenylalanine has a potent impact on SLP-76 augmentation of NFAT promoter activity.@@@@1@39@@oe@16-12-2010 889260501@GENIA Treebank@formal@@1@S@The catalytic domain of pp56(lck), but not its regulatory domain, is sufficient for inducing IL-2 production.@@@@1@19@@oe@16-12-2010 889260502@GENIA Treebank@formal@@1@S@The lymphoid src kinase pp56(lck) has been shown to be essential for the induction of different T lymphocyte responses, including CD4-mediated enhancement of Ag-induced T cell activation, early T cell differentiation, induction of IL-2 production, and cytotoxicity.@@@@1@42@@oe@16-12-2010 889260503@GENIA Treebank@formal@@1@S@It is assumed that pp56(lck) acts on these processes by phosphorylating substrates.@@@@1@13@@oe@16-12-2010 889260504@GENIA Treebank@formal@@1@S@However, it has been recently reported that the NH2 regulatory domain is sufficient to mediate CD4 accessory function.@@@@1@20@@oe@16-12-2010 889260505@GENIA Treebank@formal@@1@S@In this report we address the contribution of the regulatory and catalytic domains of pp56(lck) to another function of this enzyme independent of CD4: TCR-induced IL-2 production.@@@@1@29@@oe@16-12-2010 889260506@GENIA Treebank@formal@@1@S@Two pp56(lck) mutants lacking either the entire catalytic domain or the entire NH2 regulatory domain were generated, and their abilities to trigger transactivation of the TCR-regulated nuclear factor of activated T cells (NF-AT) region of the IL-2 promoter were compared.@@@@1@44@@oe@16-12-2010 889260507@GENIA Treebank@formal@@1@S@Only the catalytic, but not the NH2 regulatory, domain of pp56(lck) was able to induce NF-AT region transactivation on its own and to cooperate with other intracellular signals to trigger this response.@@@@1@35@@oe@16-12-2010 889260508@GENIA Treebank@formal@@1@S@Moreover, the catalytic domain of pp56(lck) was able to induce IL-2 cytokine production to an extent similar to that of wild-type pp56(lck).@@@@1@24@@oe@16-12-2010 889260509@GENIA Treebank@formal@@1@S@We conclude that different domains of the pp56(lck) molecule contribute to regulate distinct biologic functions.@@@@1@16@@oe@16-12-2010 889260510@GENIA Treebank@formal@@1@S@In fact, while the NH2 regulatory domain is sufficient to mediate CD4 accessory function, we show here that the catalytic domain of pp56(lck) is sufficient for induction of IL-2 production, mimicking TCR ligation.@@@@1@37@@oe@16-12-2010 889261001@GENIA Treebank@formal@@1@S@Isolation and characterization of murine fra-1: induction mediated by CD40 and surface Ig is protein kinase C dependent.@@@@1@20@@oe@16-12-2010 889261002@GENIA Treebank@formal@@1@S@The murine fra-1 gene, encoding Fos-related Ag 1, was isolated from a splenic cDNA library and sequenced.@@@@1@20@@oe@16-12-2010 889261003@GENIA Treebank@formal@@1@S@Murine fra-1 was highly homologous to rat and human fra-1.@@@@1@11@@oe@16-12-2010 889261004@GENIA Treebank@formal@@1@S@Oligonucleotide primers based on the murine sequence were used to construct a quantitative reverse transcription-PCR assay for gene expression.@@@@1@20@@oe@16-12-2010 889261005@GENIA Treebank@formal@@1@S@B lymphocyte stimulation via both CD40 and surface Ig (sIg) receptors substantially induced fra-1 expression, and for both receptors, induction was protein kinase C (PKC) dependent.@@@@1@33@@oe@16-12-2010 889261006@GENIA Treebank@formal@@1@S@This contrasts with induction of c-fos by both CD40 and sIg, which is PKC independent and indicates that CD40 is capable of signaling through PKC or a closely related kinase.@@@@1@32@@oe@16-12-2010 889261007@GENIA Treebank@formal@@1@S@Induction of fra-1 following engagement of CD40 did not require protein synthesis, suggesting that the PKC-dependent linkage between CD40 and fra-1 is direct.@@@@1@25@@oe@16-12-2010 889261008@GENIA Treebank@formal@@1@S@CD40-mediated fra-1 induction did require tyrosine kinase activity.@@@@1@9@@oe@16-12-2010 889261009@GENIA Treebank@formal@@1@S@These results demonstrate that CD40, like sIg, may employ PKC in producing select outcomes, that individual B cell receptors may signal downstream events via both PKC-dependent and PKC-independent pathways, and that multiple signal transduction pathways may be used to activate the expression of closely related genes.@@@@1@51@@oe@16-12-2010 889261401@GENIA Treebank@formal@@1@S@Apoptosis signaling pathways in normal T cells: differential activity of Bcl-2 and IL-1beta-converting enzyme family protease inhibitors on glucocorticoid- and Fas-mediated cytotoxicity.@@@@1@24@@oe@16-12-2010 889261402@GENIA Treebank@formal@@1@S@Fas-mediated apoptosis plays an important role in regulating the immune response in peripheral T cells.@@@@1@16@@oe@16-12-2010 889261403@GENIA Treebank@formal@@1@S@Restimulation of T cell blasts up-regulates Fas and Fas ligand expression, with subsequent interaction leading to cell death.@@@@1@20@@oe@16-12-2010 889261404@GENIA Treebank@formal@@1@S@Overexpression of Bcl-2 in tumor cells blocks apoptosis induced by many stimuli, but inhibition of Fas-mediated killing has not been consistently observed.@@@@1@24@@oe@16-12-2010 889261405@GENIA Treebank@formal@@1@S@To examine the behavior of Bcl-2 in normal cells, T cell blasts were transiently transfected with Bcl-2 and related gene products to determine the effect on apoptotic signaling.@@@@1@30@@oe@16-12-2010 889261406@GENIA Treebank@formal@@1@S@Transient overexpression of Bcl-2 in mouse and human T cell blasts did not block Fas-mediated apoptosis, whereas etoposide- and glucocorticoid-induced cytotoxicity was potently inhibited.@@@@1@26@@oe@16-12-2010 889261407@GENIA Treebank@formal@@1@S@Expression of Bcl-xL and adenovirus E1B 19K did not interfere with anti-Fas killing.@@@@1@14@@oe@16-12-2010 889261408@GENIA Treebank@formal@@1@S@In contrast, interleukin-1beta-converting enzyme family protease inhibitors Ac-DEVD-CHO and CrmA blocked Fas-mediated apoptosis.@@@@1@15@@oe@16-12-2010 889261409@GENIA Treebank@formal@@1@S@These results suggest that peripheral T cells use distinct apoptosis signaling pathways with differential sensitivity to Bcl-2 and interleukin-1beta-converting enzyme family protease inhibitors.@@@@1@24@@oe@16-12-2010 889261410@GENIA Treebank@formal@@1@S@Since T cells normally express Bcl-2 and Bcl-xL following activation, their inability to block Fas-mediated apoptosis may allow for the elimination of self-reactive cells and the appropriate regulation of immune responses.@@@@1@33@@oe@16-12-2010 889290301@GENIA Treebank@formal@@1@S@Comparative analysis identifies conserved tumor necrosis factor receptor-associated factor 3 binding sites in the human and simian Epstein-Barr virus oncogene LMP1.@@@@1@22@@oe@16-12-2010 889290302@GENIA Treebank@formal@@1@S@Nonhuman primates are naturally infected with a B-lymphotropic herpesvirus closely related to Epstein-Barr virus (EBV).@@@@1@18@@oe@16-12-2010 889290303@GENIA Treebank@formal@@1@S@These simian EBV share considerable genetic, biologic, and epidemiologic features with human EBV, including virus-induced tumorigenesis.@@@@1@20@@oe@16-12-2010 889290304@GENIA Treebank@formal@@1@S@However, latent, transformation-associated viral genes demonstrate marked sequence divergence among species despite the conserved functions.@@@@1@18@@oe@16-12-2010 889290305@GENIA Treebank@formal@@1@S@We have cloned the latent membrane protein 1 (LMP1) homologs from the simian EBV naturally infecting baboons (cercopithicine herpesvirus 12, herpesvirus papio) and rhesus monkeys (cercopithicine herpesvirus 15) for a comparative study with the human EBV oncogene.@@@@1@45@@oe@16-12-2010 889290306@GENIA Treebank@formal@@1@S@The transmembrane domains are well conserved, but there is striking sequence divergence of the carboxy-terminal cytoplasmic domain essential for B-cell immortalization and interaction with the tumor necrosis factor receptor signaling pathway.@@@@1@33@@oe@16-12-2010 889290307@GENIA Treebank@formal@@1@S@Nevertheless, the simian EBV LMP1s retain most functions in common with EBV LMP1, including the ability to induce NF-(kappa)B activity in human cells, to bind the tumor necrosis factor-associated factor 3 (TRAF3) in vitro, and to induce expression of tumor necrosis factor-responsive genes, such as ICAM1, in human B lymphocytes.@@@@1@59@@oe@16-12-2010 889290308@GENIA Treebank@formal@@1@S@Multiple TRAF3 binding sites containing a PXQXT/S core sequence can be identified in the simian EBV LMP1s by an in vitro binding assay.@@@@1@24@@oe@16-12-2010 889290309@GENIA Treebank@formal@@1@S@A PXQXT/S-containing sequence is also present in the cytoplasmic domain of the Hodgkin's disease marker, CD30, and binds TRAF3 in vitro.@@@@1@25@@oe@16-12-2010 889290310@GENIA Treebank@formal@@1@S@The last 13 amino acids containing a PXQXT/S sequence are highly conserved in human and simian EBV LMP1 but do not bind TRAF3, suggesting a distinct role for this conserved region of LMP1.@@@@1@35@@oe@16-12-2010 889290311@GENIA Treebank@formal@@1@S@The conserved TRAF3 binding sites in LMP1 and the CD30 Hodgkin's disease marker provides further evidence that a TRAF3-mediated signal transduction pathway may be important in malignant transformation.@@@@1@30@@oe@16-12-2010 889301101@GENIA Treebank@formal@@1@S@Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression.@@@@1@12@@oe@16-12-2010 889301102@GENIA Treebank@formal@@1@S@Cells need to distinguish between transient Ca2+ signals that induce events such as muscle contraction, secretion, adhesion and synaptic transmission, and sustained Ca2+ signals that are involved in cell proliferation and differentiation.@@@@1@36@@oe@16-12-2010 889301103@GENIA Treebank@formal@@1@S@The latter class of events is blocked in lymphocytes by the immunosuppressive drugs cyclosporin A and FK506, which inhibit calcineurin, a Ca2+-activated serine/threonine phosphatase necessary for the nuclear import of NF-AT transcription factors.@@@@1@36@@oe@16-12-2010 889301104@GENIA Treebank@formal@@1@S@Here we report that sustained high concentrations of Ca2+, but not transient pulses, are required to maintain NF-AT transcription factors in the nucleus, where they participate in Ca2+-dependent induction of genes required for lymphocyte activation and proliferation.@@@@1@41@@oe@16-12-2010 889301105@GENIA Treebank@formal@@1@S@Furthermore, overexpression and constitutive nuclear localization of NF-AT, but not Jun, Fos, NF-kappaB, Oct or Ets family members, renders the interleukin-2 enhancer in Jurkat T lymphocytes resistant to FK506 and cyclosporin A.@@@@1@39@@oe@16-12-2010 889301106@GENIA Treebank@formal@@1@S@Thus a primary effect of these immunosuppressive reagents is to control the subcellular localization of the NF-AT family of transcription factors.@@@@1@22@@oe@16-12-2010 889554401@GENIA Treebank@formal@@1@S@Interferons induce normal and aberrant retinoic-acid receptors type alpha in acute promyelocytic leukemia cells: potentiation of the induction of retinoid-dependent differentiation markers.@@@@1@24@@oe@16-12-2010 889554402@GENIA Treebank@formal@@1@S@Treatment of the acute promyelocytic (APL) cell line NB4 with interferon alpha (IFN(alpha)), as well as IFN(beta) and gamma, results in an increased expression of the transcripts coding for retinoic-acid receptor type alpha (RAR(alpha)) and the leukemia-specific retinoic acid receptor PML-RAR.@@@@1@50@@oe@16-12-2010 889554403@GENIA Treebank@formal@@1@S@Transcriptional induction of the RAR(alpha) and PML-RAR mRNAs is rapid and it is parallelled by an increase in the corresponding proteins.@@@@1@22@@oe@16-12-2010 889554404@GENIA Treebank@formal@@1@S@Up-regulation of RAR(alpha) and PML-RAR gene expression by IFN(alpha) is accompanied by a strong potentiation in the induction of 2 retinoid-dependent granulocytic markers, i.e., granulocyte-colony-stimulating factor receptor mRNA and leukocyte alkaline phosphatase.@@@@1@35@@oe@16-12-2010 889554405@GENIA Treebank@formal@@1@S@However, IFN(alpha) does not have any effects on the retinoid-dependent regulation of the myeloid surface markers CD11b and CD33.@@@@1@21@@oe@16-12-2010 889554406@GENIA Treebank@formal@@1@S@The IFN-dependent increase in RAR(alpha) levels and the enhancing effect of the cytokine on retinoid-dependent granulocytic markers expression may be a characteristic of PML-RAR positive cells, since the phenomena are not observed in HL-60 promyelocytes.@@@@1@37@@oe@16-12-2010 889554407@GENIA Treebank@formal@@1@S@Interferons as well as retinoids inhibit the growth of NB4 cells, although the 2 classes of compounds do not significantly interact in terms of anti-proliferative activity.@@@@1@28@@oe@16-12-2010 889554408@GENIA Treebank@formal@@1@S@These results suggest the possible use of combinations between IFNs and retinoic acid in the cyto-differentiating treatment of APL patients.@@@@1@21@@oe@16-12-2010 889624701@GENIA Treebank@formal@@1@S@Susceptibility to natural killer cells and down regulation of MHC class I expression in adenovirus 12 transformed cells are regulated by different E1A domains.@@@@1@25@@oe@16-12-2010 889624702@GENIA Treebank@formal@@1@S@All human adenoviruses transform rodent cells in vitro, but only cells transformed by serotypes belonging to subgroups A (Ad12) and B (Ad3) are tumorigenic for immunocompetent animals.@@@@1@33@@oe@16-12-2010 889624703@GENIA Treebank@formal@@1@S@In these cells, the expression of MHC-class I antigens is repressed and might allow them to escape from recognition by cytotoxic T lymphocytes (CTL) and to develop in tumor.@@@@1@33@@oe@16-12-2010 889624704@GENIA Treebank@formal@@1@S@Furthermore, these cell lines appear resistant to lysis by natural killer (NK) cells.@@@@1@17@@oe@16-12-2010 889624705@GENIA Treebank@formal@@1@S@To determine the E1A domain(s) responsible for these properties several cell lines were created by transforming baby rat kidney (BRK) cells with a set of plasmids expressing different Ad2/Ad12 hybrid E1A gene products.@@@@1@39@@oe@16-12-2010 889624706@GENIA Treebank@formal@@1@S@The MHC class 1 gene expression was inhibited in cells expressing the Ad12 13S mRNA product and in cells transformed with Ad2/Ad12 hybrid E1A gene product harboring the C-terminal part of the conserved region (CR) 3 of Ad12.@@@@1@41@@oe@16-12-2010 889624707@GENIA Treebank@formal@@1@S@Susceptibility of these transformed cell lines to NK cells was determined by cytolytic assays.@@@@1@15@@oe@16-12-2010 889624708@GENIA Treebank@formal@@1@S@The results obtained suggest that two Ad12 E1A domains are required to induce resistance of the cell lines to NK cells.@@@@1@22@@oe@16-12-2010 889645601@GENIA Treebank@formal@@1@S@An IL-2 response element in the human IL-2 receptor alpha chain promoter is a composite element that binds Stat5, Elf-1, HMG-I(Y) and a GATA family protein.@@@@1@29@@oe@16-12-2010 889645602@GENIA Treebank@formal@@1@S@Expression of the human interleukin-2 (IL-2) receptor alpha chain gene is potently upregulated by its own ligand, IL-2.@@@@1@22@@oe@16-12-2010 889645603@GENIA Treebank@formal@@1@S@In this study, we characterize an essential upstream IL-2 response element that contains both consensus and non-consensus GAS motifs, two putative Ets binding sites (EBS), one of which overlaps the consensus GAS motif, and a GATA motif, which overlaps the non-consensus GAS motif.@@@@1@51@@oe@16-12-2010 889645604@GENIA Treebank@formal@@1@S@We demonstrate that although the individual components of this element do not respond to IL-2, together they form a composite element capable of conferring IL-2 responsiveness to a heterologous promoter.@@@@1@32@@oe@16-12-2010 889645605@GENIA Treebank@formal@@1@S@Multiple factors including Stat5, Elf-1, HMG-I(Y) and GATA family proteins bind to the IL-2 response element and mutation of any one of these binding sites diminishes the activity of this element.@@@@1@34@@oe@16-12-2010 889645606@GENIA Treebank@formal@@1@S@An unidentified Ets family protein binds to the EBS overlapping the consensus GAS motif and appears to negatively regulate the human IL-2R alpha promoter.@@@@1@25@@oe@16-12-2010 889645607@GENIA Treebank@formal@@1@S@Thus, IL-2-induced IL-2R alpha promoter activity requires a complex upstream element, which appears to contain binding sites for both positive and negative regulatory factors.@@@@1@27@@oe@16-12-2010 889894801@GENIA Treebank@formal@@1@S@Tyrosine kinase and cAMP-dependent protein kinase activities in CD40-activated human B lymphocytes.@@@@1@13@@oe@16-12-2010 889894802@GENIA Treebank@formal@@1@S@In vitro, human B lymphocytes undergo long-term proliferation when activated through CD40, a protein expressed on their cell surface.@@@@1@22@@oe@16-12-2010 889894803@GENIA Treebank@formal@@1@S@The nature of CD40-dependent signals in proliferating fresh human Epstein-Barr virus-negative B lymphocytes is currently unknown.@@@@1@17@@oe@16-12-2010 889894804@GENIA Treebank@formal@@1@S@In this study, a CD40-dependent B cell culture system was used to examine the role of different signal transduction elements.@@@@1@22@@oe@16-12-2010 889894805@GENIA Treebank@formal@@1@S@Protein kinase C (PKC) depletion generated by a long-term phorbol 12 myristate 13-acetate treatment had weak effects on proliferation.@@@@1@22@@oe@16-12-2010 889894806@GENIA Treebank@formal@@1@S@Rather, tyrosine phosphorylation was shown to be directly involved in mediating CD40-dependent signals.@@@@1@15@@oe@16-12-2010 889894807@GENIA Treebank@formal@@1@S@The use of the protein tyrosine kinase (PTK)-specific inhibitor herbimycin A dramatically decreased cellular proliferation without altering the activity of the human immunodeficiency virus-1 long terminal repeat (HIV-1 LTR), a promoter largely dependent on the binding of nuclear factor kappa B (NF- kappa B).@@@@1@52@@oe@16-12-2010 889894808@GENIA Treebank@formal@@1@S@In contrast, the cAMP-dependent protein kinase specific inhibitor H-89 totally inhibited HIV-1 LTR activity at a concentration as low as 100 nM without affecting cellular proliferation.@@@@1@28@@oe@16-12-2010 889894809@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assay (EMSA) and supershift assay using an NF-kappa B binding sequence from the kappa light chain as a probe, revealed that both p65 (RelA) and c-Rel were present in CD40-stimulated B cells.@@@@1@41@@oe@16-12-2010 889894810@GENIA Treebank@formal@@1@S@While PKC depletion did not alter the NF-kappa B level, treatment of B lymphocytes with H-89 or herbimycin A provoked a decrease in the NF-kappa B level.@@@@1@29@@oe@16-12-2010 889894811@GENIA Treebank@formal@@1@S@These observations establish the importance of different signal transducing pathways leading to CD40 activation of B lymphocytes.@@@@1@18@@oe@16-12-2010 889896001@GENIA Treebank@formal@@1@S@Active suppression of the class II transactivator-encoding AIR-1 locus is responsible for the lack of major histocompatibility complex class II gene expression observed during differentiation from B cells to plasma cells.@@@@1@32@@oe@16-12-2010 889896002@GENIA Treebank@formal@@1@S@In this study the genetic control of major histocompatibility complex (MHC) class II gene expression during the transition from B cell to plasma cell has been analyzed.@@@@1@30@@oe@16-12-2010 889896003@GENIA Treebank@formal@@1@S@Class II molecules are not expressed in plasma cells because of an active suppression resulting in the abrogation of class II gene transcription.@@@@1@24@@oe@16-12-2010 889896004@GENIA Treebank@formal@@1@S@We show here that the plasma cell-specific repressor function, designated SIR (suppressor of immune response genes), does not act directly on the transcription of class II genes, but instead on the transcription of the AIR-1 gene, whose product, the class II transactivator (CIITA), is fundamental for the regulation of the constitutive and inducible expression of MHC class II genes.@@@@1@70@@oe@16-12-2010 889896005@GENIA Treebank@formal@@1@S@This was unambiguously demonstrated by the fact that plasmacytoma x B cell hybrids carrying an AIR-1 locus derived from CIITA-expressing cells do not express CIITA-specific transcripts.@@@@1@27@@oe@16-12-2010 889896006@GENIA Treebank@formal@@1@S@Transfection of a cDNA containing the human CIITA coding sequence under the control of an heterologous promoter restores expression of human MHC class II genes in the hybrids and is responsible for de novo expression of mouse MHC class II genes in both the mouse plasmacytoma cell line and the hybrids.@@@@1@52@@oe@16-12-2010 889896007@GENIA Treebank@formal@@1@S@These results confirm and extend the notion of the functional conservation of the AIR-1 gene product across species barriers.@@@@1@20@@oe@16-12-2010 889896008@GENIA Treebank@formal@@1@S@Interestingly, in CIITA-transfected cell hybrids, cell surface expression of the human HLA-DQ heterodimer was not observed.@@@@1@19@@oe@16-12-2010 889896009@GENIA Treebank@formal@@1@S@This result was not attributable to lack of HLA-DQ alpha or -DQ beta transcription, because both transcripts were present in the CIITA-transfected hybrids, although at reduced levels.@@@@1@30@@oe@16-12-2010 889896010@GENIA Treebank@formal@@1@S@These findings further support our previous observations on the distinct regulation of expression of the human HLA-DQ class II subset, which may be thus controlled at the posttranscriptional level by a CIITA-independent mechanism.@@@@1@35@@oe@16-12-2010 890037101@GENIA Treebank@formal@@1@S@Chromosome 1 aneusomy with 1p36 under-representation is related to histologic grade, DNA aneuploidy, high c-erb B-2 and loss of bcl-2 expression in ductal breast carcinoma.@@@@1@28@@oe@16-12-2010 890037102@GENIA Treebank@formal@@1@S@Chromosome 1 abnormalities with loss of 1p36 have been investigated in 95 breast-cancer samples by means of a dual-target fluorescence in-situ hybridization (FISH) technique using the pUC 1.77 and p1-79 probes, specific for the 1q12 and 1p36 regions, respectively.@@@@1@44@@oe@16-12-2010 890037103@GENIA Treebank@formal@@1@S@Abnormalities for one or both probes were detected in 83/95 samples.@@@@1@12@@oe@16-12-2010 890037104@GENIA Treebank@formal@@1@S@Relative 1p36 under-representation was found in 79/95.@@@@1@8@@oe@16-12-2010 890037105@GENIA Treebank@formal@@1@S@The clinical relevance of these alterations was studied by comparing the FISH results with several parameters currently used in breast-cancer pathology.@@@@1@22@@oe@16-12-2010 890037106@GENIA Treebank@formal@@1@S@Distinct patterns of chromosome 1 abnormalities were found among the histologic types of breast carcinoma.@@@@1@16@@oe@16-12-2010 890037107@GENIA Treebank@formal@@1@S@Lobular or mucinous samples showed few or no alterations, whereas most ductal samples had high chromosome 1 polysomy with under-representation of 1p36.@@@@1@24@@oe@16-12-2010 890037108@GENIA Treebank@formal@@1@S@In ductal carcinomas, chromosome 1 alterations increased with histologic grade, DNA aneuploidy, loss of bcl-2 and high c-erb B-2 expression.@@@@1@24@@oe@16-12-2010 890037109@GENIA Treebank@formal@@1@S@These associations were found to be statistically significant.@@@@1@9@@oe@16-12-2010 890037110@GENIA Treebank@formal@@1@S@No correlation between chromosome 1 alterations and nuclear grade, age, size, lymph-node involvement, hormonal receptor presence, proliferation activity or p53 protein expression was detected.@@@@1@30@@oe@16-12-2010 890037111@GENIA Treebank@formal@@1@S@These results indicate the utility of this FISH technique for a better definition of the biological characteristics of ductal carcinomas.@@@@1@21@@oe@16-12-2010 890156901@GENIA Treebank@formal@@1@S@Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF.@@@@1@20@@oe@16-12-2010 890156902@GENIA Treebank@formal@@1@S@Globin genes are subject to tissue-specific and developmental stage-specific regulation.@@@@1@11@@oe@16-12-2010 890156903@GENIA Treebank@formal@@1@S@A switch from human fetal (gamma)-to adult (beta)-globin expression occurs within erythroid precursor cells of the adult lineage.@@@@1@25@@oe@16-12-2010 890156904@GENIA Treebank@formal@@1@S@Previously we and others showed by targeted gene disruption that the zinc finger gene, erythroid Kruppel-like factor (EKLF), is required for expression of the beta-globin gene in mice, presumably through interaction with a high-affinity binding site in the proximal promoter.@@@@1@46@@oe@16-12-2010 890156905@GENIA Treebank@formal@@1@S@To examine the role of EKLF in the developmental regulation of the human gamma-globin gene we interbred EKLF heterozygotes (+/-) with mice harboring a human beta-globin yeast artificial chromosome transgene.@@@@1@33@@oe@16-12-2010 890156906@GENIA Treebank@formal@@1@S@We find that in the absence of EKLF, while human beta-globin expression is dramatically reduced, gamma-globin transcripts are elevated approximately 5-fold.@@@@1@24@@oe@16-12-2010 890156907@GENIA Treebank@formal@@1@S@Impaired silencing of gamma-globin expression identifies EKLF as the first transcription factor participating quantitatively in the gamma-globin to beta-globin switch.@@@@1@21@@oe@16-12-2010 890156908@GENIA Treebank@formal@@1@S@Our findings are compatible with a competitive model of switching in which EKLF mediates an adult stage-specific interaction between the beta-globin gene promoter and the locus control region that excludes the gamma-globin gene.@@@@1@34@@oe@16-12-2010 890288201@GENIA Treebank@formal@@1@S@Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications.@@@@1@16@@oe@16-12-2010 890288202@GENIA Treebank@formal@@1@S@Interleukin-12 (IL-12) is a key inducer of differentiation of uncommitted T helper (TH) cells toward the TH1 phenotype, which regulates cellular immunity, whereas IL-10 inhibits TH1 functions and potentiates TH2-regulated responses (i.e., humoral immunity).@@@@1@44@@oe@16-12-2010 890288203@GENIA Treebank@formal@@1@S@To examine the potential effects of stress on TH1/TH2 balance, we studied the ability of three prototype stress hormones-dexamethasone (a synthetic glucocorticoid) and the catecholamines norepinephrine and epinephrine-to alter the production of IL-12 (p70) and IL-10 induced by bacterial lipopolysaccharide (LPS) in human whole blood.@@@@1@57@@oe@16-12-2010 890288204@GENIA Treebank@formal@@1@S@Dexamethasone inhibited LPS-induced bioactive IL-12 production in a dose-dependent fashion and at physiologically relevant concentrations; it had no effect on IL-10 secretion.@@@@1@24@@oe@16-12-2010 890288205@GENIA Treebank@formal@@1@S@The glucocorticoid-induced reduction of IL-12 production was antagonized by RU 486, a glucocorticoid-receptor antagonist, suggesting that it was mediated by the glucocorticoid receptor.@@@@1@26@@oe@16-12-2010 890288206@GENIA Treebank@formal@@1@S@Norepinephrine and epinephrine also suppressed IL-12 production in a dose-dependent fashion and at physiological concentrations; both catecholamines, however, dose-dependently increased the production of IL-10.@@@@1@28@@oe@16-12-2010 890288207@GENIA Treebank@formal@@1@S@The effects of either catecholamine on IL-12 or IL-10 secretion were blocked completely by propranolol, a beta-adrenoreceptor antagonist, indicating that they were mediated by the beta-adrenergic receptor.@@@@1@30@@oe@16-12-2010 890288208@GENIA Treebank@formal@@1@S@These findings suggest that the central nervous system may regulate IL-12 and IL-10 secretion and, hence, TH1/TH2 balance via the peripheral end-effectors of the stress system.@@@@1@29@@oe@16-12-2010 890288209@GENIA Treebank@formal@@1@S@Thus, stress may cause a selective suppression of TH1 functions and a shift toward a TH2 cytokine pattern rather than generalized TH suppression.@@@@1@25@@oe@16-12-2010 890288210@GENIA Treebank@formal@@1@S@The TH1-to-TH2 shift may be responsible for the stress-induced susceptibility of the organism to certain infections.@@@@1@17@@oe@16-12-2010 890288211@GENIA Treebank@formal@@1@S@Through the same or a reciprocal mechanism, states associated with chronic hyperactivity or hypoactivity of the stress system might influence the susceptibility of an individual to certain autoimmune, allergic, infectious, or neoplastic diseases.@@@@1@38@@oe@16-12-2010 890346701@GENIA Treebank@formal@@1@S@Nasal NK- and T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin's disease.@@@@1@21@@oe@16-12-2010 890346702@GENIA Treebank@formal@@1@S@Nasal T/NK-cell lymphomas can be further separated into those of natural killer (NK) cell lineage or of T-cell lineage, with differences in cellular phenotype, T-cell receptor (TcR) gene rearrangement and TcR transcript expression.@@@@1@40@@oe@16-12-2010 890346703@GENIA Treebank@formal@@1@S@Both NK- and T-cell subtypes are closely associated with Epstein-Barr virus (EBV).@@@@1@15@@oe@16-12-2010 890346704@GENIA Treebank@formal@@1@S@In this study, EBV gene expression was determined in 23 cases of nasal lymphoma (NL) by in situ hybridisation (ISH), reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IH).@@@@1@39@@oe@16-12-2010 890346705@GENIA Treebank@formal@@1@S@Of the 23 cases, 19 were classified as NK-cell and 4 as T-cell tumours.@@@@1@16@@oe@16-12-2010 890346706@GENIA Treebank@formal@@1@S@ISH for EBV-encoded small non-polyadenylated RNAs showed that all cases, whether NK or T, harboured EBV in virtually all tumour cells.@@@@1@24@@oe@16-12-2010 890346707@GENIA Treebank@formal@@1@S@RT-PCR demonstrated that NL of both subtypes expressed EBNAI of the QUK splice pattern, the latent membrane proteins, LMP1 and 2 and the BamHI A rightward transcripts in the absence of EBNA2 mRNAs, compatible with the latency type II pattern.@@@@1@44@@oe@16-12-2010 890346708@GENIA Treebank@formal@@1@S@In addition, analysis of EBV protein expression by IH revealed a heterogeneous pattern of EBV gene expression at the single-cell level consisting of both LMP1+ and LMP1- tumour cells, suggesting a mixture of latency I and II.@@@@1@40@@oe@16-12-2010 890346709@GENIA Treebank@formal@@1@S@Although 2 early lytic transcripts, BZLF1 and BHRF1, were also detected in 13 and 10 cases, respectively, the lack of ZEBRA staining in any case indicates that these lytic transcripts are most likely expressed by rare cells in the biopsies entering lytic cycle.@@@@1@48@@oe@16-12-2010 890346710@GENIA Treebank@formal@@1@S@The viral transcriptional pattern similar to that of nasopharyngeal carcinoma and Hodgkin's disease suggests that EBV can exploit common regulatory mechanisms for gene transcription in diverse host cell types.@@@@1@31@@oe@16-12-2010 890346711@GENIA Treebank@formal@@1@S@Down-regulation of immunogenic proteins (EBNA2-EBNA6) in nasal lymphoma may enable tumour cells to evade host cytotoxic T-cell surveillance.@@@@1@21@@oe@16-12-2010 890555201@GENIA Treebank@formal@@1@S@Presence of a variant form of the estrogen receptor in peripheral blood mononuclear cells from normal individuals and lupus patients.@@@@1@21@@oe@16-12-2010 890555202@GENIA Treebank@formal@@1@S@Estrogen may participate in the pathogenesis of systemic lupus erythematosus (SLE) via its intracellular receptor.@@@@1@18@@oe@16-12-2010 890555203@GENIA Treebank@formal@@1@S@To investigate the presence of various isoforms of the estrogen receptor (ER) in SLE we isolated RNA from mononuclear cells of lupus patients and normal controls.@@@@1@29@@oe@16-12-2010 890555204@GENIA Treebank@formal@@1@S@Using RT-PCR we were able to identify both the full length wild-type form and an isoform of the ER which precisely lacks exon V in both patient and normal individuals.@@@@1@31@@oe@16-12-2010 890555205@GENIA Treebank@formal@@1@S@Our results, although limited, suggest that normal individuals can express both the wild-type and truncated version at the same time, whereas lupus patients only express either the wild-type or the truncated ER.@@@@1@36@@oe@16-12-2010 890555206@GENIA Treebank@formal@@1@S@This finding may lead to a better understanding of the reasons for the prevalence of lupus in females and of the estrogenic effects on SLE disease activity.@@@@1@28@@oe@16-12-2010 890680501@GENIA Treebank@formal@@1@S@Lack of IL-12 signaling in human allergen-specific Th2 cells.@@@@1@10@@oe@16-12-2010 890680502@GENIA Treebank@formal@@1@S@IL-12 is a powerful skewer of CD4+ T cell responses toward the Th1 phenotype by inducing IFN-gamma production in naive Th cells.@@@@1@23@@oe@16-12-2010 890680503@GENIA Treebank@formal@@1@S@In the present study we addressed the question of whether IL-12 can reverse established Th2 responses into Th1/Th0 responses by inducing IFN-gamma production in memory Th2 cells.@@@@1@28@@oe@16-12-2010 890680504@GENIA Treebank@formal@@1@S@To this aim, allergen-specific CD4+ T cell clones (TCC) were generated from the peripheral blood of three atopic patients, and their cytokine profiles were analyzed.@@@@1@30@@oe@16-12-2010 890680505@GENIA Treebank@formal@@1@S@The majority of these TCC exhibited a strongly polarized Th2 cytokine profile, and the production of IFN-gamma could not be induced by exogenous IL-12.@@@@1@26@@oe@16-12-2010 890680506@GENIA Treebank@formal@@1@S@Only those TCC with low IFN-gamma levels in the absence of IL-12 responded to IL-12 by additional enhancement of IFN-gamma production.@@@@1@22@@oe@16-12-2010 890680507@GENIA Treebank@formal@@1@S@The IL-12 nonresponsiveness of the Th2 clones was further evident by the total lack of IL-12-induced phosphorylation of STAT4 (signal transducer and activator of transcription-4), a transcription factor that is typically involved in IL-12 signaling.@@@@1@39@@oe@16-12-2010 890680508@GENIA Treebank@formal@@1@S@Consequently, IL-12 also failed to induce the DNA-binding activity of STAT4-containing complexes in the nuclei of these Th2 clones.@@@@1@21@@oe@16-12-2010 890680509@GENIA Treebank@formal@@1@S@All TCC expressed equal levels of the low-affinity IL-12R beta1 subunit.@@@@1@12@@oe@16-12-2010 890680510@GENIA Treebank@formal@@1@S@Our results indicate that human allergen-specific Th cells with strongly polarized Th2 cytokine profiles do not respond to IL-12 and, therefore, cannot be induced to produce IFN-gamma.@@@@1@31@@oe@16-12-2010 890680511@GENIA Treebank@formal@@1@S@The apparent high frequency of IL-12-nonresponsive Th cells within the allergen-specific populations in atopic patients predicts a limited skewing potential of IL-12 in the case of established Th2 responses, but only affecting newly recruited naive Th cells.@@@@1@39@@oe@16-12-2010 891036001@GENIA Treebank@formal@@1@S@Characterization of a CD43/leukosialin-mediated pathway for inducing apoptosis in human T-lymphoblastoid cells.@@@@1@13@@oe@16-12-2010 891036002@GENIA Treebank@formal@@1@S@The monoclonal antibody (mAb) J393 induces apoptosis in Jurkat T-cells.@@@@1@13@@oe@16-12-2010 891036003@GENIA Treebank@formal@@1@S@NH2-terminal amino acid sequence analysis identified the 140-kDa surface antigen for mAb J393 as CD43/leukosialin, the major sialoglycoprotein of leukocytes.@@@@1@22@@oe@16-12-2010 891036004@GENIA Treebank@formal@@1@S@While Jurkat cells co-expressed two discrete cell-surface isoforms of CD43, recognized by mAb J393 and mAb G10-2, respectively, only J393/CD43 signaled apoptosis.@@@@1@26@@oe@16-12-2010 891036005@GENIA Treebank@formal@@1@S@J393/CD43 was found to be hyposialylated, bearing predominantly O-linked monosaccharide glycans, whereas G10-2/CD43 bore complex sialylated tetra- and hexasaccharide chains.@@@@1@23@@oe@16-12-2010 891036006@GENIA Treebank@formal@@1@S@Treatment with soluble, bivalent mAb J393 killed 25-50% of the cell population, while concomitant engagement of either the CD3.TcR complex or the integrins CD18 and CD29 significantly potentiated this effect.@@@@1@34@@oe@16-12-2010 891036007@GENIA Treebank@formal@@1@S@Treatment of Jurkat cells with mAb J393 induced tyrosine phosphorylation of specific protein substrates that underwent hyperphosphorylation upon antigen receptor costimulation.@@@@1@22@@oe@16-12-2010 891036008@GENIA Treebank@formal@@1@S@Tyrosine kinase inhibition by herbimycin A diminished J393/CD43-mediated apoptosis, whereas inhibition of phosphotyrosine phosphatase activity by bis(maltolato)oxovanadium-IV enhanced cell death.@@@@1@22@@oe@16-12-2010 891036009@GENIA Treebank@formal@@1@S@Signal transduction through tyrosine kinase activation may lead to altered gene expression, as J393/CD43 ligation prompted decreases in the nuclear localization of the transcriptional regulatory protein NF-kappaB and proteins binding the interferon-inducible regulatory element.@@@@1@36@@oe@16-12-2010 891036010@GENIA Treebank@formal@@1@S@Since peripheral blood T-lymphocytes express cryptic epitopes for mAb J393, these findings demonstrate the existence of a tightly regulated CD43-mediated pathway for inducing apoptosis in human T-cell lineages.@@@@1@30@@oe@16-12-2010 891039801@GENIA Treebank@formal@@1@S@Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain.@@@@1@17@@oe@16-12-2010 891039802@GENIA Treebank@formal@@1@S@Recent work has shown that IL-10 induces activation of the JAK-STAT signaling pathway.@@@@1@14@@oe@16-12-2010 891039803@GENIA Treebank@formal@@1@S@To define the mechanism underlying signal transducer and activator of transcription (STAT) protein recruitment to the interleukin 10 (IL-10) receptor, the STAT proteins activated by IL-10 in different cell populations were first defined using electrophoretic mobility shift assays.@@@@1@44@@oe@16-12-2010 891039804@GENIA Treebank@formal@@1@S@In all cells tested, IL-10 activated Stat1 and Stat3 and induced the formation of three distinct DNA binding complexes that contained different combinations of these two transcription factors.@@@@1@30@@oe@16-12-2010 891039805@GENIA Treebank@formal@@1@S@IL-10 also activated Stat5 in Ba/F3 cells that stably expressed the murine IL-10 receptor.@@@@1@15@@oe@16-12-2010 891039806@GENIA Treebank@formal@@1@S@Using a structure-function mutagenesis approach, two tyrosine residues (Tyr427 and Tyr477) in the intracellular domain of the murine IL-10 receptor were found to be redundantly required for receptor function and for activation of Stat3 but not for Stat1 or Stat5.@@@@1@44@@oe@16-12-2010 891039807@GENIA Treebank@formal@@1@S@Twelve amino acid peptides encompassing either of these two tyrosine residues in phosphorylated form coprecipitated Stat3 but not Stat1 and blocked IL-10-induced Stat3 phosphorylation in a cell-free system.@@@@1@29@@oe@16-12-2010 891039808@GENIA Treebank@formal@@1@S@In contrast, tyrosine-phosphorylated peptides containing Tyr374 or Tyr396 did not interact with Stat3 or block Stat3 activation.@@@@1@19@@oe@16-12-2010 891039809@GENIA Treebank@formal@@1@S@These data demonstrate that Stat3 but not Stat1 or Stat5 is directly recruited to the ligand-activated IL-10 receptor by binding to specific but redundant receptor intracellular domain sequences containing phosphotyrosine.@@@@1@31@@oe@16-12-2010 891039810@GENIA Treebank@formal@@1@S@This study thus supports the concept that utilization of distinct STAT proteins by different cytokine receptors is dependent on the expression of particular ligand-activatable, tyrosine-containing STAT docking sites in receptor intracellular domains.@@@@1@34@@oe@16-12-2010 891057701@GENIA Treebank@formal@@1@S@Identification and characterization of a leukocyte-specific component of the nuclear body.@@@@1@12@@oe@16-12-2010 891057702@GENIA Treebank@formal@@1@S@The nuclear body (NB) is a cellular organelle that is involved in the pathogenesis of acute promyelocytic leukemia and viral infection.@@@@1@24@@oe@16-12-2010 891057703@GENIA Treebank@formal@@1@S@The NB is also a target of antibodies in the serum of patients with the autoimmune disease primary biliary cirrhosis.@@@@1@21@@oe@16-12-2010 891057704@GENIA Treebank@formal@@1@S@In this study, serum from a patient with primary biliary cirrhosis was used to identify a cDNA encoding a novel component of the NB, a 140-kDa protein designated Sp140.@@@@1@32@@oe@16-12-2010 891057705@GENIA Treebank@formal@@1@S@The predicted amino acid sequence of the amino-terminal portion of Sp140 was similar to Sp100, a previously identified NB protein.@@@@1@22@@oe@16-12-2010 891057706@GENIA Treebank@formal@@1@S@The carboxyl portion of Sp140 contained a zinc-finger domain and a bromodomain, motifs that are present in proteins regulating gene transcription.@@@@1@23@@oe@16-12-2010 891057707@GENIA Treebank@formal@@1@S@High levels of Sp140 mRNA were detected in human spleen and peripheral blood leukocytes, but not other human tissues.@@@@1@21@@oe@16-12-2010 891057708@GENIA Treebank@formal@@1@S@The level of SP140 mRNA in myeloid precursor cell lines HL60 and NB4 markedly increased in response to chemically induced cellular differentiation.@@@@1@23@@oe@16-12-2010 891057709@GENIA Treebank@formal@@1@S@Immunohistochemical techniques were used to demonstrate that SP140 localized to the NB in differentiated HL60 and NB4 cells.@@@@1@19@@oe@16-12-2010 891057710@GENIA Treebank@formal@@1@S@The location of Sp140 in the NB, and expression of this gene in cells involved in host defense, suggest that Sp140 may be involved in the pathogenesis of acute promyelocytic leukemia and viral infection.@@@@1@37@@oe@16-12-2010 891284201@GENIA Treebank@formal@@1@S@T-cell-directed TAL-1 expression induces T-cell malignancies in transgenic mice.@@@@1@10@@oe@16-12-2010 891284202@GENIA Treebank@formal@@1@S@The TAL-1 gene specifies for a basic domain-helix-loop-helix protein, which is involved in the control of normal hematopoiesis.@@@@1@20@@oe@16-12-2010 891284203@GENIA Treebank@formal@@1@S@In human pathology, the TAL-1 gene product is expressed in a high percentage of T-cell acute lymphoblastic leukemias in the pediatric age range; however, it has not been established whether the expression has a causal role in oncogenesis.@@@@1@42@@oe@16-12-2010 891284204@GENIA Treebank@formal@@1@S@In this report, we describe the phenotype of mouse transgenic lines obtained by inducing tal-1 protein expression in lymphoid tissues using the LCK promoter.@@@@1@26@@oe@16-12-2010 891284205@GENIA Treebank@formal@@1@S@The survival rate of tal-1 transgenic animals was much lower as compared with control mice.@@@@1@16@@oe@16-12-2010 891284206@GENIA Treebank@formal@@1@S@Histopathological analysis revealed lymphomas of T-cell type, often comprising a minor B-cell component.@@@@1@15@@oe@16-12-2010 891284207@GENIA Treebank@formal@@1@S@Some mice showed marked splenic lymphocyte depletion.@@@@1@8@@oe@16-12-2010 891284208@GENIA Treebank@formal@@1@S@Primary lymphocyte cultures showed partial independence from exogenous growth stimuli and increased resistance to low-serum apoptosis.@@@@1@17@@oe@16-12-2010 891284209@GENIA Treebank@formal@@1@S@To further unravel the tal-1 oncogenic potential, a strain of tal-1 transgenic mice was crossbred with p53-/- mice; the survival rate in these animals was reduced by more than one-half when compared with that of tal-1 mice, and histopathological analysis revealed exclusively T-cell lymphomas.@@@@1@48@@oe@16-12-2010 891284210@GENIA Treebank@formal@@1@S@These data indicate that TAL-1, expressed in T cells, is per se a potent oncogene, which may exert a key leukemogenetic role in the majority of T-cell acute lymphoblastic leukemias.@@@@1@34@@oe@16-12-2010 891288801@GENIA Treebank@formal@@1@S@Naive (CD45RA+) T lymphocytes are more sensitive to oxidative stress-induced signals than memory (CD45RO+) cells.@@@@1@20@@oe@16-12-2010 891288802@GENIA Treebank@formal@@1@S@Formation of reactive oxygen intermediates (ROI) after oxidative stress has been shown to be an activation signal for T lymphocytes, e.g., expression of IL-2 and its receptor are induced.@@@@1@34@@oe@16-12-2010 891288803@GENIA Treebank@formal@@1@S@These ROI-induced effects can, to a large extent, be attributed to the activation of the transcription factor NF-kappaB.@@@@1@21@@oe@16-12-2010 891288804@GENIA Treebank@formal@@1@S@Now we have examined whether naive and memory T lymphocytes differ in their sensitivity to ROI-mediated signals.@@@@1@18@@oe@16-12-2010 891288805@GENIA Treebank@formal@@1@S@When CD45RA+ (naive) and CD45RO+ (memory) T lymphocytes were directly stimulated with H2O2, NF-kappaB nuclear translocation was stronger in naive cells than in memory cells and it could be induced with lower doses.@@@@1@39@@oe@16-12-2010 891288806@GENIA Treebank@formal@@1@S@The composition of the induced nuclear NF-kappaB (levels of p50 and RelA proteins) was similar in these cell types.@@@@1@22@@oe@16-12-2010 891288807@GENIA Treebank@formal@@1@S@The magnitude and kinetics of intracellular ROI were similar, suggesting that there were no differences in ROI-forming mechanisms or antioxidative capacities.@@@@1@23@@oe@16-12-2010 891288808@GENIA Treebank@formal@@1@S@The probable regulatory point was the cytoplasmic IkappaB inhibitor: in CD45RA+ cells, H2O2 caused a more profound depression in the levels of IkappaB alpha.@@@@1@27@@oe@16-12-2010 891288809@GENIA Treebank@formal@@1@S@These findings indicate that T cells representing different activation and/or differentiation stages can be differentially responsive to ROI-mediated signals.@@@@1@20@@oe@16-12-2010 891387101@GENIA Treebank@formal@@1@S@Potent gene regulatory and antiproliferative activities of 20-methyl analogues of 1,25 dihydroxyvitamin D3.@@@@1@14@@oe@16-12-2010 891387102@GENIA Treebank@formal@@1@S@The biological active form of vitamin D3, 1,25-dihydroxyvitamin D3 (VD), regulates cellular growth and differentiation.@@@@1@20@@oe@16-12-2010 891387103@GENIA Treebank@formal@@1@S@This provides the hormone with an interesting therapeutic potential.@@@@1@10@@oe@16-12-2010 891387104@GENIA Treebank@formal@@1@S@However, hypercalcemia is a side effect, which is caused by VD's classical action, the regulation of calcium homeostasis.@@@@1@23@@oe@16-12-2010 891387105@GENIA Treebank@formal@@1@S@This made the need for VD analogues with selectively increased cell regulatory properties.@@@@1@14@@oe@16-12-2010 891387106@GENIA Treebank@formal@@1@S@Studies with 20-epi analogues pointed out the importance of the carbon-20 position and led to the development of 20-methyl derivatives of VD.@@@@1@23@@oe@16-12-2010 891387107@GENIA Treebank@formal@@1@S@In this report the biological properties of the compounds ZK161422 and ZK157202, which are 20-methyl- and 20-methyl-23-eneanalogues, respectively, have been analyzed in comparison with VD.@@@@1@29@@oe@16-12-2010 891387108@GENIA Treebank@formal@@1@S@Both compounds show about 2-fold lower affinity to the VD receptor (VDR) than VD.@@@@1@17@@oe@16-12-2010 891387109@GENIA Treebank@formal@@1@S@However, compared to VD, their antiproliferative effect is up to 30-fold higher on human peripheral blood mononuclear cells and even up to 300-fold higher on human breast cancer MCF-7 cells.@@@@1@33@@oe@16-12-2010 891387110@GENIA Treebank@formal@@1@S@Whereas the hypercalcemic effect for ZK157202 is also increased 10-fold, ZK161422 has the same calcium-mobilizing potency as VD.@@@@1@20@@oe@16-12-2010 891387111@GENIA Treebank@formal@@1@S@Moreover, ZK161422, but not ZK157202, showed preference for gene activation from a promoter carrying a VD response element with a palindromic arrangement of two hexameric receptor binding sites spaced by 9 nucleotides (IP9) rather than for activation from a response element formed by a direct repeat spaced by 3 nucleotides (DR3).@@@@1@59@@oe@16-12-2010 891387112@GENIA Treebank@formal@@1@S@This observation supports a model, in which promoter selectivity reflects the selectively increased antiproliferative effect of VD analogues.@@@@1@20@@oe@16-12-2010 891695901@GENIA Treebank@formal@@1@S@Interferon augments PML and PML/RAR alpha expression in normal myeloid and acute promyelocytic cells and cooperates with all-trans retinoic acid to induce maturation of a retinoid-resistant promyelocytic cell line.@@@@1@30@@oe@16-12-2010 891695902@GENIA Treebank@formal@@1@S@The PML gene is fused to the retinoic acid receptor alpha gene (RAR alpha) in the acute promyelocytic leukemia (APL) 15; 17 translocation.@@@@1@29@@oe@16-12-2010 891695903@GENIA Treebank@formal@@1@S@PML is expressed in diverse tissues and cell lines and localized in the nucleus with a typical speckled pattern.@@@@1@20@@oe@16-12-2010 891695904@GENIA Treebank@formal@@1@S@In the bone marrow, it is preferentially expressed in myeloid cells.@@@@1@13@@oe@16-12-2010 891695905@GENIA Treebank@formal@@1@S@PML appears to be transcriptionally regulated by class I and II interferons, which raises the possibility that interferons modulate the function and growth and differentiation potential of normal myeloid cells and precursors by activating PML-dependent pathways.@@@@1@38@@oe@16-12-2010 891695906@GENIA Treebank@formal@@1@S@Similarly, interferons could act on APL cells, alone or in combination with all-trans retinoic acid (RA), especially if the PML/RAR alpha fusion transcript that results from the t(15; 17) is induced by interferon.@@@@1@38@@oe@16-12-2010 891695907@GENIA Treebank@formal@@1@S@We report here that PML is expressed at low levels or not expressed in normal circulating human monocytes, lymphocytes, and polymorphonucleate cells, but is markedly induced by interferon; that PML and PML/RAR alpha expression is augmented by interferon in the NB4 APL cell line, which carries the t(15; 17), and in APL blasts from patients; that interferon inhibits growth and survival of NB4 APL cells in cooperation with RA; that interferons alone have minimal maturation effect on NB4 cells; and, finally, that interferon gamma, but not alpha or beta, induces maturation and growth suppression of NB4 cells with de novo retinoid resistance, and partially restores RA response.@@@@1@121@@oe@16-12-2010 891697001@GENIA Treebank@formal@@1@S@Generation of CD1+RelB+ dendritic cells and tartrate-resistant acid phosphatase-positive osteoclast-like multinucleated giant cells from human monocytes.@@@@1@17@@oe@16-12-2010 891697002@GENIA Treebank@formal@@1@S@We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) stimulate the differentiation of human monocytes into two phenotypically distinct types of macrophages.@@@@1@31@@oe@16-12-2010 891697003@GENIA Treebank@formal@@1@S@However, in vivo, not only CSF but also many other cytokines are produced under various conditions.@@@@1@19@@oe@16-12-2010 891697004@GENIA Treebank@formal@@1@S@Those cytokines may modulate the differentiation of monocytes by CSFs.@@@@1@11@@oe@16-12-2010 891697005@GENIA Treebank@formal@@1@S@In the present study, we showed that CD14+ adherent human monocytes can differentiate into CD1+relB+ dendritic cells (DC) by the combination of GM-CSF plus interleukin-4 (IL-4) and that they differentiate into tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like multinucleated giant cells (MGC) by the combination of M-CSF plus IL-4.@@@@1@58@@oe@16-12-2010 891697006@GENIA Treebank@formal@@1@S@However, the monocyte-derived DC were not terminally differentiated cells; they could still convert to macrophages in response to M-CSF.@@@@1@22@@oe@16-12-2010 891697007@GENIA Treebank@formal@@1@S@Tumor necrosis factor-alpha (TNF-alpha) stimulated the terminal differentiation of the DC by downregulating the expression of the M-CSF receptor, cfms mRNA, and aborting the potential to convert to macrophages.@@@@1@34@@oe@16-12-2010 891697008@GENIA Treebank@formal@@1@S@In contrast to IL-4, interferon-gamma (IFN-gamma) had no demonstrable effect on the differentiation of monocytes.@@@@1@19@@oe@16-12-2010 891697009@GENIA Treebank@formal@@1@S@Rather, IFN-gamma antagonized the effect of IL-4 and suppressed the DC and MGC formation induced by GM-CSF + IL-4 and M-CSF + IL-4, respectively.@@@@1@27@@oe@16-12-2010 891697010@GENIA Treebank@formal@@1@S@Taken together, these results provide a new aspect to our knowledge of monocyte differentiation and provide evidence that human monocytes are flexible in their differentiation potential and are precursors not only of macrophages but also of CD1+relB+DC and TRAP-positive MGC.@@@@1@42@@oe@16-12-2010 891697011@GENIA Treebank@formal@@1@S@Such a diverse pathway of monocyte differentiation may constitute one of the basic mechanisms of immune regulation.@@@@1@18@@oe@16-12-2010 891964401@GENIA Treebank@formal@@1@S@Regulation of [Ca2+]i rise activated by doxepin-sensitive H1-histamine receptors in Jurkat cells, cloned human T lymphocytes.@@@@1@18@@oe@16-12-2010 891964402@GENIA Treebank@formal@@1@S@To clarify the presence of histamine receptor and its transmembrane mechanism in human T lymphocytes, we investigated the effects of agonists or antagonists of histamine receptor subtypes and bacterial toxins on intracellular concentration of Ca2+ [Ca2+]i), [3H]pyrilamine binding and c-fos mRNA expression in Jurkat cells, cloned human T lymphocytes.@@@@1@54@@oe@16-12-2010 891964403@GENIA Treebank@formal@@1@S@H1-agonists (histamine and 2-methylhistamine) caused a transient rise of [Ca2+], and H1-antagonists (pyrilamine and doxepin) inhibited the histamine-induced [Ca2+]i rise more potently than the H2-antagonist (cimetidine) on the H3-antagonist (impromidine).@@@@1@40@@oe@16-12-2010 891964404@GENIA Treebank@formal@@1@S@Binding parameters of [3H]pyrilamine binding were Kd = 5.53 nM and Bmax = 2,647 sites/cell.@@@@1@18@@oe@16-12-2010 891964405@GENIA Treebank@formal@@1@S@Pretreatment with B.pertussis, V.cholera. or C.botulinum toxin did not influence histamine-induced [Ca2+]i rise.@@@@1@15@@oe@16-12-2010 891964406@GENIA Treebank@formal@@1@S@Western Blot analysis using antibodies against subunits of GTP-binding proteins indicated that Gq/G11 richly existed in Jurkat cells.@@@@1@19@@oe@16-12-2010 891964407@GENIA Treebank@formal@@1@S@Histamine induced mRNA expression of an immediate early gene c-fos.@@@@1@11@@oe@16-12-2010 891964408@GENIA Treebank@formal@@1@S@Pretreatment with a protein kinase C activator, phorbol 12-myristate 13-acetate, caused almost complete inhibition of histamine-induced [Ca2+]i rise, but did not do so by activators of cAMP- and cGMP-dependent protein kinases.@@@@1@35@@oe@16-12-2010 892086701@GENIA Treebank@formal@@1@S@T cell response to Epstein-Barr virus transactivators in chronic rheumatoid arthritis.@@@@1@12@@oe@16-12-2010 892086702@GENIA Treebank@formal@@1@S@Rheumatoid arthritis is a multistep disorder associated with autoimmune features of yet unknown etiology.@@@@1@15@@oe@16-12-2010 892086703@GENIA Treebank@formal@@1@S@Implication of viruses such as Epstein-Barr virus (EBV) in rheumatoid arthritis pathogenesis has been suspected on the basis of several indirect observations, but thus far, a direct link between EBV and rheumatoid arthritis has not been provided.@@@@1@42@@oe@16-12-2010 892086704@GENIA Treebank@formal@@1@S@Here we show that a large fraction of T cells infiltrating affected joints from a patient with chronic rheumatoid arthritis recognizes two EBV transactivators (BZLF1 and BMLF1) in a major histocompatibility complex-restricted fashion.@@@@1@36@@oe@16-12-2010 892086705@GENIA Treebank@formal@@1@S@Responses to these EBV antigens by synovial lymphocytes from several other chronic rheumatoid arthritis patients were readily detectable.@@@@1@19@@oe@16-12-2010 892086706@GENIA Treebank@formal@@1@S@Thus these results suggest a direct contribution of EBV to chronic rheumatoid arthritis pathogenesis.@@@@1@15@@oe@16-12-2010 892086707@GENIA Treebank@formal@@1@S@They also demonstrate for the first time the occurrence of T cell responses against EBV transactivating factors, which might be central in the control of virus reactivation.@@@@1@29@@oe@16-12-2010 892193701@GENIA Treebank@formal@@1@S@Differential nuclear localization of p50, p52, and RelB proteins in human accessory cells of the immune response in situ.@@@@1@22@@oe@16-12-2010 892193702@GENIA Treebank@formal@@1@S@The Rel/NF-kappa B proteins, p50, p52, p65, c-Rel, and RelB, constitute a family of transcription factors involved in the positive regulation of a variety of genes during the immune response.@@@@1@37@@oe@16-12-2010 892193703@GENIA Treebank@formal@@1@S@Recently, it has been shown that RelB knockout mice have no dendritic cells (DC).@@@@1@18@@oe@16-12-2010 892193704@GENIA Treebank@formal@@1@S@An overexpression of p50 has been described in follicular dendritic cells (FDC).@@@@1@15@@oe@16-12-2010 892193705@GENIA Treebank@formal@@1@S@A constitutive NF-kappa B activity has been reported in mature macrophages.@@@@1@12@@oe@16-12-2010 892193706@GENIA Treebank@formal@@1@S@This led to the hypothesis that some of the Rel/NF-kappa B proteins were key nuclear factors in functions of accessory cells of the immune response.@@@@1@26@@oe@16-12-2010 892193707@GENIA Treebank@formal@@1@S@Therefore, we investigated in situ the nuclear localization of Rel/NF-kappa B proteins in accessory cells of the immune system by immunohistochemistry and double labeling by immunofluorescence from five normal human tonsils and five lymph nodes with follicular hyperplasia.@@@@1@40@@oe@16-12-2010 892193708@GENIA Treebank@formal@@1@S@Nuclear p65 and c-Rel proteins were found in all cell types including lymphocytes.@@@@1@14@@oe@16-12-2010 892193709@GENIA Treebank@formal@@1@S@In germinal centers GC, p50, p52, and RelB were found in the nuclei of FDC only and were not detected in the nuclei of CD68+ cells.@@@@1@30@@oe@16-12-2010 892193710@GENIA Treebank@formal@@1@S@In T cell areas, p50, p52, and RelB were found in the nuclei of HLA-DR+ cells with an antigen-presenting cell (APC) morphology.@@@@1@28@@oe@16-12-2010 892193711@GENIA Treebank@formal@@1@S@p52 and RelB were detected in the nuclei in both CD1a+ and CD68+ cells from the T cell area, whereas p50 was found only in CD68- and CD1a- cells.@@@@1@31@@oe@16-12-2010 892193712@GENIA Treebank@formal@@1@S@Cells with nuclear p50 were negative for the CD38, CD20 and CD2 markers.@@@@1@15@@oe@16-12-2010 892193713@GENIA Treebank@formal@@1@S@These results show that, physiologically, high levels of nuclear of p50, p52 and RelB are restricted to accessory cells of the immune system, which include FDC in GC, and DC and macrophages in the T cell zone, that specialized scavenger macrophages from GC do not have detectable levels of p52 and RelB, whereas macrophages from the T cell area, known to present the antigen to T cells, do have both nuclear p52 and RelB, and that in the T cell zone, p52 and RelB are located in nuclei of both CD1a+, CD68+ or both, cells APC, whereas p50 is restricted to CD1a- and CD68- APC.@@@@1@120@@oe@16-12-2010 892193714@GENIA Treebank@formal@@1@S@The different patterns of p50, p52 and RelB protein nuclear localization may provide insight into their different roles during the immune response in vivo.@@@@1@26@@oe@16-12-2010 892247401@GENIA Treebank@formal@@1@S@Cloning and expression of the Epstein-Barr virus-encoded dUTPase: patients with acute, reactivated or chronic virus infection develop antibodies against the enzyme.@@@@1@24@@oe@16-12-2010 892247402@GENIA Treebank@formal@@1@S@The gene encoding the Epstein-Barr virus (EBV)-specific dUTPase was amplified from virus DNA by PCR.@@@@1@19@@oe@16-12-2010 892247403@GENIA Treebank@formal@@1@S@The active enzyme was expressed in Escherichia coli and in insect cells as a non-fusion protein.@@@@1@17@@oe@16-12-2010 892247404@GENIA Treebank@formal@@1@S@The protein from E. coli specifically converted dUTP to dUMP and did not react with other dNTPs or NTPs.@@@@1@20@@oe@16-12-2010 892247405@GENIA Treebank@formal@@1@S@Preliminary experiments yielded a Km value of about 0.8 microM for dUTP.@@@@1@13@@oe@16-12-2010 892247406@GENIA Treebank@formal@@1@S@MAbs against the dUTPase reacted with a protein of approximately 31 kDa in 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-stimulated B cells harbouring either type 1 or type 2 EBV.@@@@1@29@@oe@16-12-2010 892247407@GENIA Treebank@formal@@1@S@The protein was found in untreated cells at low levels, whereas induction of the lytic replication cycle by TPA treatment or by providing the immediate early transactivator BZLF1 in trans resulted in increased expression.@@@@1@36@@oe@16-12-2010 892247408@GENIA Treebank@formal@@1@S@We demonstrated that the virus dUTPase isolated from EBV-infected cells is a phosphoprotein.@@@@1@14@@oe@16-12-2010 892247409@GENIA Treebank@formal@@1@S@The protein expressed in insect cells was used to test for the presence of specific antibodies in sera from normal, healthy carriers and from patients with various diseases.@@@@1@30@@oe@16-12-2010 892247410@GENIA Treebank@formal@@1@S@While the sera of EBV-negative individuals (0/3) or healthy carriers (0/33) did not contain detectable levels of antibodies, patients with mononucleosis (5/18), chronic EBV infection (2/7), EBV reactivation (7/20) and human immunodeficiency virus infection (5/24) showed elevated antibody titres against the enzyme.@@@@1@58@@oe@16-12-2010 892247411@GENIA Treebank@formal@@1@S@This indicated that the dUTPase is expressed during EBV replication and reactivation.@@@@1@13@@oe@16-12-2010 892247412@GENIA Treebank@formal@@1@S@The enzyme might therefore be a potential target for drug therapy under conditions of active DNA replication.@@@@1@18@@oe@16-12-2010 892590401@GENIA Treebank@formal@@1@S@Second messenger up-regulation of androgen receptor gene transcription is absent in androgen insensitive human prostatic carcinoma cell lines, PC-3 and DU-145.@@@@1@23@@oe@16-12-2010 892590402@GENIA Treebank@formal@@1@S@A theoretical pathway of transcriptional regulation of the androgen receptor (AR) gene is via a cAMP response element (CRE) present in its promoter region (-508 to -501).@@@@1@34@@oe@16-12-2010 892590403@GENIA Treebank@formal@@1@S@After 20 h of stimulation with 8-bromo-cAMP, AR mRNA was upregulated in LNCaP but not in either PC-3 or DU-145 cell lines.@@@@1@24@@oe@16-12-2010 892590404@GENIA Treebank@formal@@1@S@We have demonstrated that the level of CRE binding protein (CREB) was the same in all cell lines and that the putative AR-CRE forms specific and compatible protein interactions with CREB.@@@@1@34@@oe@16-12-2010 892590405@GENIA Treebank@formal@@1@S@The ability to regulate AR gene transcription via the second messenger pathway is lost in the PC-3 and DU-145 cell lines.@@@@1@22@@oe@16-12-2010 892590406@GENIA Treebank@formal@@1@S@This may be an important primary mechanism of androgen insensitivity in prostate cancer.@@@@1@14@@oe@16-12-2010 892945901@GENIA Treebank@formal@@1@S@Prostaglandin E2 induction of binding activity to CRE and AP-2 elements in human T lymphocytes.@@@@1@16@@oe@16-12-2010 892945902@GENIA Treebank@formal@@1@S@Prostaglandins of the E series are immunomodulatory agents which exert inhibitory as well as stimulatory effects on a variety of immune responses.@@@@1@23@@oe@16-12-2010 892945903@GENIA Treebank@formal@@1@S@Since it is known that PGE2 is able to increase cAMP levels, we investigated whether it can affect gene expression through the activation of the transcription factors which bind enhancer elements in the promoter regions of cAMP-regulated genes.@@@@1@40@@oe@16-12-2010 892945904@GENIA Treebank@formal@@1@S@Using electrophoretic mobility shift assay, we demonstrated that a short treatment of human T lymphocytes with PGE2 induces specific binding activity to CRE and AP-2, but not AP-1, DNA elements.@@@@1@34@@oe@16-12-2010 892945905@GENIA Treebank@formal@@1@S@Since the okadaic acid, a potent protein phosphatase inhibitor, prolongs the induction of the binding activity, phosphorylation events are likely to occur.@@@@1@26@@oe@16-12-2010 892945906@GENIA Treebank@formal@@1@S@This activity seems to be due to increased cAMP levels because forskolin and IBMX mimic the effects of PGE2.@@@@1@20@@oe@16-12-2010 892945907@GENIA Treebank@formal@@1@S@More interestingly, transfection experiments with CRE-CAT plasmide show that PGE2 activates the transcription of a CRE-containing promoter.@@@@1@19@@oe@16-12-2010 892945908@GENIA Treebank@formal@@1@S@These data support the positive role for PGE2 on some immune functions.@@@@1@13@@oe@16-12-2010 892954601@GENIA Treebank@formal@@1@S@Regulation of cytokine and cytokine receptor expression by glucocorticoids.@@@@1@10@@oe@16-12-2010 892954602@GENIA Treebank@formal@@1@S@Glucocorticoids (GCS) profoundly inhibit several aspects of T cell immunity largely through inhibition of cytokine expression at the transcriptional and posttranscriptional levels.@@@@1@25@@oe@16-12-2010 892954603@GENIA Treebank@formal@@1@S@GCS were also reported to act indirectly by inducing transforming growth factor-beta expression, which in turn blocks T cell immunity.@@@@1@22@@oe@16-12-2010 892954604@GENIA Treebank@formal@@1@S@In exerting their antiproliferative effects, GCS diffuse into target cells where they bind their cytoplasmic receptor, which in turn translocates to the nucleus where it inhibits transcription of cytokine genes through direct binding to the glucocorticoid response elements (GRE), which are located in the promoter region of cytokine genes or, alternatively, through antagonism of the action of transcription factors required for optimal transcriptional activation.@@@@1@72@@oe@16-12-2010 892954605@GENIA Treebank@formal@@1@S@In contrast to their inhibitory effects on cytokine expression, GCS up-regulate cytokine receptor expression that correlates with enhanced cytokine effects on target cells.@@@@1@25@@oe@16-12-2010 892954606@GENIA Treebank@formal@@1@S@In this review, we summarize the current state of knowledge of the mechanism of action of GCS, including the phenomenon of steroid-induced rebound, which ensues upon GCS withdrawal.@@@@1@32@@oe@16-12-2010 893013101@GENIA Treebank@formal@@1@S@The Oct-2 transcription factor.@@@@1@5@@oe@16-12-2010 893013102@GENIA Treebank@formal@@1@S@The Oct-2 transcription factor is a member of the POU (Pit-Oct-Unc) family of transcription factors and is expressed only in B lymphocytes and in neuronal cells but not in other cell types.@@@@1@35@@oe@16-12-2010 893013103@GENIA Treebank@formal@@1@S@The primary RNA transcript of the gene is subject to alternative splicing to yield different variants which can either activate or repress gene expression.@@@@1@25@@oe@16-12-2010 893013104@GENIA Treebank@formal@@1@S@The forms produced in B lymphocytes have a predominantly activating effect on gene expression whereas those produced in neuronal cells have a predominantly inhibitory effect and can repress the expression of both the herpes simplex virus immediate-early genes and the cellular tyrosine hydroxylase gene.@@@@1@45@@oe@16-12-2010 893013105@GENIA Treebank@formal@@1@S@Thus Oct-2 plays an important role in the regulation of cellular gene expression in both B cells and neuronal cells as well as in the control of viral latency.@@@@1@30@@oe@16-12-2010 893351801@GENIA Treebank@formal@@1@S@Tissue and cell-type specific expression of the tuberous sclerosis gene, TSC2, in human tissues.@@@@1@17@@oe@16-12-2010 893351802@GENIA Treebank@formal@@1@S@TSC2 is a gene on chromosome 16p13.3 associated with the autosomal dominant neurocutaneous disorder, tuberous sclerosis complex (TSC).@@@@1@22@@oe@16-12-2010 893351803@GENIA Treebank@formal@@1@S@By using a partial nucleotide sequence from the cloned TSC2 and polymerase chain reaction methodology, we constructed a digoxigenin-labeled complementary DNA probe to examine TSC2 gene expression in autopsy- or biopsy-derived human tissues by in situ hybridization.@@@@1@39@@oe@16-12-2010 893351804@GENIA Treebank@formal@@1@S@TSC2 messenger RNA was widely expressed in various cell types throughout the body, including epithelia, lymphocytes, and cells with endocrine functions, e.g., adrenal cortex and anterior pituitary.@@@@1@33@@oe@16-12-2010 893351805@GENIA Treebank@formal@@1@S@It was prominently and selectively (within the central nervous system) expressed in pyramidal cells of the cerebral cortex and other motor neurons, e.g., in spinal cord and brainstem nuclei.@@@@1@34@@oe@16-12-2010 893351806@GENIA Treebank@formal@@1@S@Visceral TSC2 expression was comparable in autopsy tissues from patients with and without TSC; TSC2 messenger RNA expression was most prominent in cells with a rapid mitotic rate and turnover, e.g., epithelia and lymphocytes, with central nervous system pyramidal cells and other neurons being an obvious exception, and/or in cells with important secretory/transport functions.@@@@1@60@@oe@16-12-2010 893351807@GENIA Treebank@formal@@1@S@This widespread expression of the TSC2 gene supports the view that it encodes a protein vital to cell growth and metabolism or one that functions as a tumor/growth suppressor.@@@@1@30@@oe@16-12-2010 893454201@GENIA Treebank@formal@@1@S@Cell specific expression of human Bruton's agammaglobulinemia tyrosine kinase gene (Btk) is regulated by Sp1- and Spi-1/PU.1-family members.@@@@1@22@@oe@16-12-2010 893454202@GENIA Treebank@formal@@1@S@Bruton's agammaglobulinemia tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase involved in the human disease X-linked agammaglobulinemia (XLA).@@@@1@24@@oe@16-12-2010 893454203@GENIA Treebank@formal@@1@S@The gene is expressed in all hematopoietic cells with the exception of T-cells and plasma cells.@@@@1@17@@oe@16-12-2010 893454204@GENIA Treebank@formal@@1@S@For this expression pattern the first 280 bp upstream of the major transcriptional start site seems to be sufficient.@@@@1@20@@oe@16-12-2010 893454205@GENIA Treebank@formal@@1@S@In vitro footprinting analysis within this part of the promoter revealed two Sp1 binding sites as well as a PU-box.@@@@1@21@@oe@16-12-2010 893454206@GENIA Treebank@formal@@1@S@The transcription factor Spi-1/PU.1 as well as the closely related factor Spi-B bound to the PU-box in B-cells.@@@@1@19@@oe@16-12-2010 893454207@GENIA Treebank@formal@@1@S@In the erythroleukemia cell line K562, due to the absence of Spi-B, only PU.1 bound to the Btk promoter.@@@@1@22@@oe@16-12-2010 893454208@GENIA Treebank@formal@@1@S@Mutation of either site reduced the expression in transient transfection experiments.@@@@1@12@@oe@16-12-2010 893454209@GENIA Treebank@formal@@1@S@However, mutation of the PU box had no effect in the T-cell line Jurkat, where none of the Spi-1 family members is expressed.@@@@1@26@@oe@16-12-2010 893454210@GENIA Treebank@formal@@1@S@In addition Spi-B as well as PU.1 were able to transactivate Btk expression.@@@@1@14@@oe@16-12-2010 893454211@GENIA Treebank@formal@@1@S@In fetal liver of PU.1-/- mice, which lack lymphoid and myeloid cells, expression of Btk was reduced two- to threefold but not abolished.@@@@1@26@@oe@16-12-2010 893454212@GENIA Treebank@formal@@1@S@Collectively this study shows that expression of the Btk gene is regulated by the combined action of Sp1- and PU.1-family members.@@@@1@22@@oe@16-12-2010 894324301@GENIA Treebank@formal@@1@S@The proximal regulatory element of the interferon-gamma promoter mediates selective expression in T cells.@@@@1@15@@oe@16-12-2010 894324302@GENIA Treebank@formal@@1@S@Interferon-gamma (IFN-gamma) is produced by natural killer cells and certain subsets of T cells, but the basis for its selective expression is unknown.@@@@1@27@@oe@16-12-2010 894324303@GENIA Treebank@formal@@1@S@Within the region between -108 and -40 base pairs of the IFN-gamma promoter are two conserved and essential regulatory elements, which confer activation-specific expression in T cells.@@@@1@29@@oe@16-12-2010 894324304@GENIA Treebank@formal@@1@S@This report describes studies indicating that the most proximal of these two regulatory elements is an important determinant of its restricted expression.@@@@1@23@@oe@16-12-2010 894324305@GENIA Treebank@formal@@1@S@The proximal element is a composite site that binds members of the CREB/ATF, AP-1, and octamer families of transcription factors.@@@@1@23@@oe@16-12-2010 894324306@GENIA Treebank@formal@@1@S@Jun is essential for activation-induced transcription and binds preferably as a heterodimer with ATF-2.@@@@1@15@@oe@16-12-2010 894324307@GENIA Treebank@formal@@1@S@In contrast, CREB appears to dampen transcription from this element.@@@@1@12@@oe@16-12-2010 894324308@GENIA Treebank@formal@@1@S@The CpG dinucleotide in this element is selectively methylated in Th2 T cells and other cells that do not express IFN-gamma, and methylation markedly reduces transcription factor binding.@@@@1@30@@oe@16-12-2010 894324309@GENIA Treebank@formal@@1@S@As a target for DNA methylation and for binding of transcription factors that mediate or impede transcription, this element appears to play a central role in controlling IFN-gamma expression.@@@@1@31@@oe@16-12-2010 894333801@GENIA Treebank@formal@@1@S@Elf-1 and Stat5 bind to a critical element in a new enhancer of the human interleukin-2 receptor alpha gene [published erratum appears in Mol Cell Biol 1997 Apr;17(4):2351]@@@@1@37@@oe@16-12-2010 894333802@GENIA Treebank@formal@@1@S@The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is a key regulator of lymphocyte proliferation.@@@@1@18@@oe@16-12-2010 894333803@GENIA Treebank@formal@@1@S@IL-2R alpha is rapidly and potently induced in T cells in response to mitogenic stimuli.@@@@1@16@@oe@16-12-2010 894333804@GENIA Treebank@formal@@1@S@Interleukin 2 (IL-2) stimulates IL-2R alpha transcription, thereby amplifying expression of its own high-affinity receptor.@@@@1@19@@oe@16-12-2010 894333805@GENIA Treebank@formal@@1@S@IL-2R alpha transcription is at least in part controlled by two positive regulatory regions, PRRI and PRRII.@@@@1@19@@oe@16-12-2010 894333806@GENIA Treebank@formal@@1@S@PRRI is an inducible proximal enhancer, located between nucleotides -276 and -244, which contains NF-kappaB and SRE/CArG motifs.@@@@1@21@@oe@16-12-2010 894333807@GENIA Treebank@formal@@1@S@PRRII is a T-cell-specific enhancer, located between nucleotides -137 and -64, which binds the T-cell-specific Ets protein Elf-1 and HMG-I(Y) proteins.@@@@1@24@@oe@16-12-2010 894333808@GENIA Treebank@formal@@1@S@However, none of these proximal regions account for the induction of IL-2R alpha transcription by IL-2.@@@@1@18@@oe@16-12-2010 894333809@GENIA Treebank@formal@@1@S@To find new regulatory regions of the IL-2R alpha gene, 8.5 kb of the 5' end noncoding sequence of the IL-2R alpha gene have been sequenced.@@@@1@28@@oe@16-12-2010 894333810@GENIA Treebank@formal@@1@S@We identified an 86-nucleotide fragment that is 90% identical to the recently characterized murine IL-2-responsive element (mIL-2rE).@@@@1@21@@oe@16-12-2010 894333811@GENIA Treebank@formal@@1@S@This putative human IL-2rE, designated PRRIII, confers IL-2 responsiveness on a heterologous promoter.@@@@1@16@@oe@16-12-2010 894333812@GENIA Treebank@formal@@1@S@PRRIII contains a Stat protein binding site that overlaps with an EBS motif (GASd/EBSd).@@@@1@17@@oe@16-12-2010 894333813@GENIA Treebank@formal@@1@S@These are essential for IL-2 inducibility of PRRIII/CAT reporter constructs.@@@@1@11@@oe@16-12-2010 894333814@GENIA Treebank@formal@@1@S@IL-2 induced the binding of Stat5a and b proteins to the human GASd element.@@@@1@15@@oe@16-12-2010 894333815@GENIA Treebank@formal@@1@S@To confirm the physiological relevance of these findings, we carried out in vivo footprinting experiments which showed that stimulation of IL-2R alpha expression correlated with occupancy of the GASd element.@@@@1@32@@oe@16-12-2010 894333816@GENIA Treebank@formal@@1@S@Our data demonstrate a major role of the GASd/EBSd element in IL-2R alpha regulation and suggest that the T-cell-specific Elf-1 factor can serve as a transcriptional repressor.@@@@1@28@@oe@16-12-2010 894336501@GENIA Treebank@formal@@1@S@Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation.@@@@1@24@@oe@16-12-2010 894336502@GENIA Treebank@formal@@1@S@The Epstein-Barr virus (EBV) transforming protein LMP1 appears to be a constitutively activated tumor necrosis factor receptor (TNFR) on the basis of an intrinsic ability to aggregate in the plasma membrane and an association of its cytoplasmic carboxyl terminus (CT) with TNFR-associated factors (TRAFs).@@@@1@53@@oe@16-12-2010 894336503@GENIA Treebank@formal@@1@S@We now show that in EBV-transformed B lymphocytes most of TRAF1 or TRAF3 and 5% of TRAF2 are associated with LMP1 and that most of LMP1 is associated with TRAF1 or TRAF3.@@@@1@34@@oe@16-12-2010 894336504@GENIA Treebank@formal@@1@S@TRAF1, TRAF2, and TRAF3 bind to a single site in the LMP1 CT corresponding to amino acids (aa) 199 to 214, within a domain which is important for B-lymphocyte growth transformation (aa 187 to 231).@@@@1@43@@oe@16-12-2010 894336505@GENIA Treebank@formal@@1@S@Further deletional and alanine mutagenesis analyses and comparison with TRAF binding sequences in CD40, in CD30, and in the LMP1 of other lymphycryptoviruses provide the first evidence that PXQXT/S is a core TRAF binding motif.@@@@1@38@@oe@16-12-2010 894336506@GENIA Treebank@formal@@1@S@The negative effects of point mutations in the LMP1(1-231) core TRAF binding motif on TRAF binding and NF-kappaB activation genetically link the TRAFs to LMP1(1-231)-mediated NF-kappaB activation.@@@@1@28@@oe@16-12-2010 894336507@GENIA Treebank@formal@@1@S@NF-kappaB activation by LMP1(1-231) is likely to be mediated by TRAF1/TRAF2 heteroaggregates since TRAF1 is unique among the TRAFs in coactivating NF-kappaB with LMP1(1-231), a TRAF2 dominant-negative mutant can block LMP1(1-231)-mediated NF-kappaB activation as well as TRAF1 coactivation, and 30% of TRAF2 is associated with TRAF1 in EBV-transformed B cells.@@@@1@54@@oe@16-12-2010 894336508@GENIA Treebank@formal@@1@S@TRAF3 is a negative modulator of LMP1(1-231)-mediated NF-kappaB activation.@@@@1@10@@oe@16-12-2010 894336509@GENIA Treebank@formal@@1@S@Surprisingly, TRAF1, -2, or -3 does not interact with the terminal LMP1 CT aa 333 to 386 which can independently mediate NF-kappaB activation.@@@@1@27@@oe@16-12-2010 894336510@GENIA Treebank@formal@@1@S@The constitutive association of TRAFs with LMP1 through the aa 187 to 231 domain which is important in NF-kappaB activation and primary B-lymphocyte growth transformation implicates TRAF aggregation in LMP1 signaling.@@@@1@32@@oe@16-12-2010 894338901@GENIA Treebank@formal@@1@S@CD40, but not lipopolysaccharide and anti-IgM stimulation of primary B lymphocytes, leads to a persistent nuclear accumulation of RelB.@@@@1@22@@oe@16-12-2010 894338902@GENIA Treebank@formal@@1@S@In this study we analyzed the effect of CD40 stimulation on the activity and nuclear appearance of Rel/nuclear factor kappaB (NF-kappaB) factors in primary murine B lymphocytes.@@@@1@30@@oe@16-12-2010 894338903@GENIA Treebank@formal@@1@S@We show that triggering of CD40 signaling pathway(s) by CD40 ligands expressed on L cells led to strong activation of an NF-kappaB-controlled beta-globin reporter gene in primary B lymphocytes from transgenic mice.@@@@1@36@@oe@16-12-2010 894338904@GENIA Treebank@formal@@1@S@Analyses of nuclear translocation of individual members of Rel proteins after CD40 induction of primary B cells showed a strong and long-lasting accumulation of RelB and, less pronounced, of c-Rel.@@@@1@33@@oe@16-12-2010 894338905@GENIA Treebank@formal@@1@S@LPS stimulation did not give rise to a persistent nuclear accumulation of RelB and c-Rel, whereas nuclear c-Rel, but not RelB, accumulated after B cell receptor stimulation.@@@@1@31@@oe@16-12-2010 894338906@GENIA Treebank@formal@@1@S@CD40 induced not only nuclear translocation but also de novo synthesis of RelB RNA and protein.@@@@1@17@@oe@16-12-2010 894338907@GENIA Treebank@formal@@1@S@S107 plasmacytoma cells, which express CD40 but are defective for the nuclear appearance of p50/p65-NF-kappaB, do not express RelB after CD40 stimulation.@@@@1@25@@oe@16-12-2010 894338908@GENIA Treebank@formal@@1@S@In S107 cells stably transfected with relB genes, stimulation of nuclear RelB translocation by CD40 was observed.@@@@1@19@@oe@16-12-2010 894338909@GENIA Treebank@formal@@1@S@These results indicate that stimulation of CD40 signaling pathways exerts a long-lasting stimulatory effect on both the transcription and nuclear translocation of RelB.@@@@1@24@@oe@16-12-2010 894338910@GENIA Treebank@formal@@1@S@Since LPS and anti-IgM were unable to activate RelB, CD40 appears to trigger a special program of gene expression involved in the proliferation and/or differentiation of B lymphocytes.@@@@1@30@@oe@16-12-2010 894751201@GENIA Treebank@formal@@1@S@Sterol dependent LDL-receptor gene transcription in lymphocytes from normal and CML patients.@@@@1@13@@oe@16-12-2010 894751202@GENIA Treebank@formal@@1@S@Sterol regulatory element (SRE) has been recognized to regulate various key genes coding for especially low density lipoprotein (LDL)-receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase known to play a crucial role in the cholesterol feedback mechanism.@@@@1@47@@oe@16-12-2010 894751203@GENIA Treebank@formal@@1@S@The deranged cholesterol feedback mechanism has been widely recognised in initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML).@@@@1@28@@oe@16-12-2010 894751204@GENIA Treebank@formal@@1@S@Consequently, the present study was addressed to understand this phenomenon and revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects as well as its absence in lymphocytes from untreated CML patients.@@@@1@45@@oe@16-12-2010 894751205@GENIA Treebank@formal@@1@S@However, this factor appeared when the CML patients achieved complete haematological remission (CHR) through alpha-interferon therapy.@@@@1@20@@oe@16-12-2010 894751206@GENIA Treebank@formal@@1@S@Further, an inverse relationship was also observed between sterol modulated LDL-receptor gene transcription and the binding affinity of this 47 kDa factor to the SRE sequence.@@@@1@28@@oe@16-12-2010 894751207@GENIA Treebank@formal@@1@S@Based upon these results we propose that alpha-interferon through its receptor initiates phosphatidic acid dependent signalling which in turn regulates the affinity of 47 kDa sterol regulatory element binding factor as well as LDL-receptor gene transcription in lymphocytes from CML patients.@@@@1@42@@oe@16-12-2010 895002901@GENIA Treebank@formal@@1@S@Effects of Ara-C on neutral sphingomyelinase and mitogen- and stress- activated protein kinases in T-lymphocyte cell lines.@@@@1@17@@oe@16-12-2010 895002902@GENIA Treebank@formal@@1@S@Neutral sphingomyelinase (SMase) can be activated by extracellular signals to produce ceramide, which may affect mitogen-activated protein kinase (MAPK) activities.@@@@1@26@@oe@16-12-2010 895002903@GENIA Treebank@formal@@1@S@Neutral SMase activity was assessed in membranes from Jurkat, a human T-cell line, and EL4, a murine T-cell line.@@@@1@23@@oe@16-12-2010 895002904@GENIA Treebank@formal@@1@S@Ara-C activated SMase with 10 minutes in both Jurkat and EL4 cells, while phorbol ester (PMA) had no effect.@@@@1@23@@oe@16-12-2010 895002905@GENIA Treebank@formal@@1@S@PMA, but not Ara-C or ceramides, activated ERK MAPKS, in Jurkat and EL4.@@@@1@17@@oe@16-12-2010 895002906@GENIA Treebank@formal@@1@S@PMA acted synergistically with ionomycin to activate JNK MAPKs in Jurkat and EL4 within 10 minutes.@@@@1@17@@oe@16-12-2010 895002907@GENIA Treebank@formal@@1@S@Ara-C activated JNKs only after prolonged incubation (90-120 minutes).@@@@1@12@@oe@16-12-2010 895002908@GENIA Treebank@formal@@1@S@Thus, ceramide is not a positive signal for ERK activation in T-cell lines.@@@@1@15@@oe@16-12-2010 895002909@GENIA Treebank@formal@@1@S@The effects of Ara-C on JNK activity may be mediated through secondary response pathways.@@@@1@15@@oe@16-12-2010 895097701@GENIA Treebank@formal@@1@S@Expression of Egr-1 correlates with the transformed phenotype and the type of viral latency in EBV genome positive lymphoid cell lines.@@@@1@22@@oe@16-12-2010 895097702@GENIA Treebank@formal@@1@S@In this paper we have investigated the role of Egr-1 in B cell growth regulation by examining the gene expression in a panel of B cell lines, including both EBV genome negative and EBV carrying cell lines.@@@@1@39@@oe@16-12-2010 895097703@GENIA Treebank@formal@@1@S@Egr-1 expression correlates with the cellular phenotype and the specific pattern of viral latency established within the individual cell lines.@@@@1@21@@oe@16-12-2010 895097704@GENIA Treebank@formal@@1@S@Thus, constitutive activation of Egr-1 gene is invariably associated with unrestricted expression of viral latent genes in all group III EBV genome carrying cell lines.@@@@1@27@@oe@16-12-2010 895097705@GENIA Treebank@formal@@1@S@In contrast, Egr-1 expression is abrogated in group I Burkitt tumor cells, irrespective of the EBV genome carrying status.@@@@1@22@@oe@16-12-2010 895097706@GENIA Treebank@formal@@1@S@Activated viral gene expression associated with phenotypic conversion of group I cell lines in to group II or III restores the Egr-1 gene expression.@@@@1@25@@oe@16-12-2010 895097707@GENIA Treebank@formal@@1@S@Several forms of EGR-1 protein are found within the different groups of cell lines, and the binding activity to DNA consensus sequences was investigated.@@@@1@26@@oe@16-12-2010 895097708@GENIA Treebank@formal@@1@S@Finally, time course analysis of Egr-1 expression during the early steps of EBV infection in vitro demonstrated that Egr-1 is upregulated within minutes from the initial interaction with the B lymphocyte.@@@@1@33@@oe@16-12-2010 895500001@GENIA Treebank@formal@@1@S@HIV-1 LTR activity in human CD40-activated B lymphocytes is dependent on NF-kappaB.@@@@1@13@@oe@16-12-2010 895500002@GENIA Treebank@formal@@1@S@CD40-stimulated human B lymphocytes are highly permissive to a productive infection by the human immunodeficiency virus type 1.@@@@1@19@@oe@16-12-2010 895500003@GENIA Treebank@formal@@1@S@In these cells, nuclear factors involved in activation of the HIV-1 LTR, which contains the transcriptional control elements of the virus, are unknown.@@@@1@27@@oe@16-12-2010 895500004@GENIA Treebank@formal@@1@S@Transient expression assays with plasmids containing deleted parts of the LTR region linked to a reporter gene showed that the NF-kappaB binding site was essential for HIV-1 LTR activity in CD40-stimulated B lymphocytes.@@@@1@34@@oe@16-12-2010 895500005@GENIA Treebank@formal@@1@S@In addition, electrophoretic mobility shift and supershift assays revealed that important NF-kappaB binding activity composed of at least p50, p65, and c-Rel NF-kappaB subunits was present in nuclei of CD40-stimulated B cells.@@@@1@36@@oe@16-12-2010 895500006@GENIA Treebank@formal@@1@S@These results confirm at a molecular level the ability of HIV-1 to replicate in B cells and that this activity is strongly associated with NF-kappaB.@@@@1@26@@oe@16-12-2010 895509401@GENIA Treebank@formal@@1@S@Mutation of tyrosines 492/493 in the kinase domain of ZAP-70 affects multiple T-cell receptor signaling pathways.@@@@1@17@@oe@16-12-2010 895509402@GENIA Treebank@formal@@1@S@The protein-tyrosine kinase ZAP-70 is implicated, together with the Src kinase p56(lck), in controlling the early steps of the T-cell antigen receptor (TCR) signaling cascade.@@@@1@30@@oe@16-12-2010 895509403@GENIA Treebank@formal@@1@S@To help elucidate further the mechanism by which ZAP-70 regulates these initial events, we used a dominant-negative mutant approach.@@@@1@21@@oe@16-12-2010 895509404@GENIA Treebank@formal@@1@S@We overexpressed in the Jurkat T-cell line ZAP-70 mutated on Tyr-492 and Tyr-493 in the putative regulatory loop of its kinase domain.@@@@1@23@@oe@16-12-2010 895509405@GENIA Treebank@formal@@1@S@This mutant inhibited TCR-induced activation of nuclear factor of activated T cells by interfering with both intracellular calcium increase and Ras-regulated activation of extracellular signal-regulated kinases.@@@@1@27@@oe@16-12-2010 895509406@GENIA Treebank@formal@@1@S@Moreover, TCR-induced phosphorylation of pp36-38, thought to play a role upstream of these pathways, was found to be reduced.@@@@1@23@@oe@16-12-2010 895509407@GENIA Treebank@formal@@1@S@In contrast, overexpression of wild-type ZAP-70 induced constitutive activation of nuclear factor of activated T cells.@@@@1@18@@oe@16-12-2010 895509408@GENIA Treebank@formal@@1@S@The ZAP-70 mutant studied here could be phosphorylated on tyrosine when associated to the TCR zeta chain and was able to bind p56(lck).@@@@1@24@@oe@16-12-2010 895509409@GENIA Treebank@formal@@1@S@This result demonstrates that Tyr-492 and Tyr-493 are not responsible for the Src homology domain 2-mediated association of p56(lck) with ZAP-70.@@@@1@22@@oe@16-12-2010 895509410@GENIA Treebank@formal@@1@S@Our data are most consistent with a model in which recruitment to the TCR allows ZAP-70 autophosphorylation and binding to p56(lck), which in turn phosphorylates Tyr-492 and/or Tyr-493 with consequent up-regulation of the ZAP-70 kinase activity.@@@@1@38@@oe@16-12-2010 895509411@GENIA Treebank@formal@@1@S@ZAP-70 will then be able to effectively control phosphorylation of its substrates and lead to gene activation.@@@@1@18@@oe@16-12-2010 895517301@GENIA Treebank@formal@@1@S@Activation of nuclear factor-kappaB via T cell receptor requires a Raf kinase and Ca2+ influx.@@@@1@16@@oe@16-12-2010 895517302@GENIA Treebank@formal@@1@S@Functional synergy between Raf and calcineurin.@@@@1@7@@oe@16-12-2010 895517303@GENIA Treebank@formal@@1@S@Signals transduced via the TCR activate the transcription factor nuclear factor-kappaB (NF-kappaB), which, in turn, is critical to the transcriptional induction of many genes important for the proliferation and expression of a differentiated phenotype.@@@@1@40@@oe@16-12-2010 895517304@GENIA Treebank@formal@@1@S@Treatment of T cells with the protein kinase C activator PMA in combination with Ca2+ ionophores mimics this process, and the two agents are often substituted for TCR stimulation, bypassing the TCR.@@@@1@35@@oe@16-12-2010 895517305@GENIA Treebank@formal@@1@S@Here we identify intracellular signaling components involved in activation of NF-kappaB following TCR stimulation.@@@@1@15@@oe@16-12-2010 895517306@GENIA Treebank@formal@@1@S@TCR signaling was triggered by treating Jurkat T cells with PHA or anti-CD3 Abs, and NF-kappaB activation was monitored by electrophoretic mobility shift assays and/or by kappaB-dependent reporter assays.@@@@1@31@@oe@16-12-2010 895517307@GENIA Treebank@formal@@1@S@Contrary to the idea that protein kinase C is involved in TCR-mediated activation of NF-kappaB, high doses of staurosporine did not interfere with activation of NF-kappaB by PHA, while the same dose of staurosporine completely blocked activation by PMA.@@@@1@42@@oe@16-12-2010 895517308@GENIA Treebank@formal@@1@S@PHA-induced kappaB-dependent reporter activity was, however, effectively blocked by a dominant negative form of Raf-1, suggesting a critical role for a Raf kinase.@@@@1@27@@oe@16-12-2010 895517309@GENIA Treebank@formal@@1@S@The TCR-mediated activation of NF-kappaB was also dependent on a Ca2+ influx, because the Ca2+ channel blocker, SK&F 96365, as well as other agents that prevented the Ca2+ influx, inhibited NF-kappaB activation.@@@@1@37@@oe@16-12-2010 895517310@GENIA Treebank@formal@@1@S@Cotransfection of a constitutively active form of calcineurin largely substituted for the Ca2+ requirement and reversed the blockade by SK&F 96365.@@@@1@22@@oe@16-12-2010 895517311@GENIA Treebank@formal@@1@S@Consistent with these observations, coexpression of constitutively active forms of Raf-1 and calcineurin synergistically induced kappaB-dependent reporter activity, suggesting a physiologically relevant functional interaction between the kinase and the phosphatase.@@@@1@33@@oe@16-12-2010 895521201@GENIA Treebank@formal@@1@S@Induction of the CD11b gene during activation of the monocytic cell line U937 requires a novel nuclear factor MS-2 [published erratum appears in J Immunol 1999 Jul 15;163(2):1091]@@@@1@37@@oe@16-12-2010 895521202@GENIA Treebank@formal@@1@S@The differentiation of myeloid precursors into mature myelomonocytic cells is characterized by the induction of the gene encoding the beta2 integrin CD11b.@@@@1@23@@oe@16-12-2010 895521203@GENIA Treebank@formal@@1@S@The transcription factors Sp1 and PU.1 prime the CD11b promoter, but the nature of the factors responsible for its inducible expression are unknown.@@@@1@25@@oe@16-12-2010 895521204@GENIA Treebank@formal@@1@S@In addition to the CD11b gene, the homologous genes encoding CD11a and CD11c also exhibit inducible expression during myeloid differentiation.@@@@1@22@@oe@16-12-2010 895521205@GENIA Treebank@formal@@1@S@Therefore, we compared the nucleotide sequences of the CD11a, CD11b, and CD11c gene promoters to identify common elements that might contribute to inducible expression.@@@@1@28@@oe@16-12-2010 895521206@GENIA Treebank@formal@@1@S@This analysis identified one such element repeated four times within the CD11b promoter.@@@@1@14@@oe@16-12-2010 895521207@GENIA Treebank@formal@@1@S@Mutation of these elements indicated that two, MS-2beta and MS-2gamma, are critical to the induction of the CD11b gene during differentiation of the pro-monocytic cell line U937.@@@@1@30@@oe@16-12-2010 895521208@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assays indicate that MS-2beta and MS-2gamma interact with nuclear factors that are induced during U937 differentiation.@@@@1@20@@oe@16-12-2010 895521209@GENIA Treebank@formal@@1@S@These factors are detected at the time the CD11b promoter is activated.@@@@1@13@@oe@16-12-2010 895521210@GENIA Treebank@formal@@1@S@The molecular mass of these factors is approximately 28 kDa, and their DNA binding characteristics are indistinguishable from those of the novel nuclear factor MS-2.@@@@1@27@@oe@16-12-2010 895521211@GENIA Treebank@formal@@1@S@Taken together, our data indicate that MS-2 mediates induction of the CD11b gene as cells of the monocytic lineage mature.@@@@1@22@@oe@16-12-2010 895521212@GENIA Treebank@formal@@1@S@The presence of multiple potential binding sites for MS-2 in the promoter regions of a wide range of genes expressed in mature myeloid cells suggests this factor plays a general role in myeloid differentiation.@@@@1@35@@oe@16-12-2010 895923901@GENIA Treebank@formal@@1@S@Dexamethasone suppression test: corticosteroid receptors regulation in mononuclear leukocytes of young and aged subjects.@@@@1@16@@oe@16-12-2010 895923902@GENIA Treebank@formal@@1@S@The dexamethasone suppression test (DST) is considered an indicator of the function of the adrenal pituitary axis.@@@@1@20@@oe@16-12-2010 895923903@GENIA Treebank@formal@@1@S@The effect of the steroid is mediated by its binding to corticosteroid receptors.@@@@1@14@@oe@16-12-2010 895923904@GENIA Treebank@formal@@1@S@We previously suggested that the measurement of corticosteroid receptors in lymphocytes is an index of an analogous pattern in brain.@@@@1@21@@oe@16-12-2010 895923905@GENIA Treebank@formal@@1@S@In the present study, corticosteroid Type I and Type II receptors in mononuclear leukocytes were measured in 10 elderly subjects and in 9 young adults, before and after overnight DST (1 mg).@@@@1@37@@oe@16-12-2010 895923906@GENIA Treebank@formal@@1@S@Receptors were measured by radioreceptor assay.@@@@1@7@@oe@16-12-2010 895923907@GENIA Treebank@formal@@1@S@In all the subjects, dexamethasone was able to suppress plasma cortisol.@@@@1@13@@oe@16-12-2010 895923908@GENIA Treebank@formal@@1@S@The number of Type I and Type II receptors before the test was lower in elderly subjects than in adults.@@@@1@21@@oe@16-12-2010 895923909@GENIA Treebank@formal@@1@S@In the control group, dexamethasone produced a significant depression of Type I receptors (from 267 +/- 72 to 169 +/- 71 receptors per cell), which can be interpreted as a primary involvement of Type I receptors in the response to dexamethasone; Type II receptors decreased in half the subjects (from 2849 +/- 703 to 2345 +/- 569 receptors per cell).@@@@1@68@@oe@16-12-2010 895923910@GENIA Treebank@formal@@1@S@In elderly healthy subjects, Type II receptors were also significantly decreased (from 1796 +/- 671 to 720 +/- 345).@@@@1@23@@oe@16-12-2010 895923911@GENIA Treebank@formal@@1@S@We suggest that in young subjects Type II receptors are initially up-regulated by dexamethasone, and then down-regulated, while in aged subjects an up-regulation cannot be achieved, as suggested by the higher values of plasma cortisol usually found in aging subjects.@@@@1@45@@oe@16-12-2010 896011201@GENIA Treebank@formal@@1@S@Lymphocytes from CML patients lack a 47 kDa factor having affinity for a genomic sterol regulatory sequence.@@@@1@18@@oe@16-12-2010 896011202@GENIA Treebank@formal@@1@S@Deranged cellular cholesterol homeostasis has been widely recognized in the initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML).@@@@1@28@@oe@16-12-2010 896011203@GENIA Treebank@formal@@1@S@Since the human genomic sterol regulatory element (SRE) has been shown to regulate various key genes involved in this phenomenon, the present study revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects, as well as its absence in lymphocytes from untreated CML patients.@@@@1@60@@oe@16-12-2010 896011204@GENIA Treebank@formal@@1@S@However, this factor appeared when these CML patients achieved complete haematological remission (CHR) through alpha-interferon therapy.@@@@1@20@@oe@16-12-2010 896011205@GENIA Treebank@formal@@1@S@Furthermore, an inverse relationship was also observed between the LDL receptor gene expression at the transcriptional level and the binding affinity of this 47 kDa protein factor to the SRE sequence.@@@@1@33@@oe@16-12-2010 896011206@GENIA Treebank@formal@@1@S@Based upon these results we propose that this factor may have a role in pathophysiology of chronic myeloid leukaemia.@@@@1@20@@oe@16-12-2010