862779101@GENIA Treebank@formal@@1@S@Efficient transcription and replication of simian immunodeficiency virus in the absence of NF-kappaB and Sp1 binding elements.@@@@1@18@@oe@16-12-2010 862779102@GENIA Treebank@formal@@1@S@Ten mutants of the simian immunodeficiency virus (SIV) SIVmac239 bearing deletions (delta) or substitutions (subst) in the NF-kappaB and/or Sp1 binding elements were created, and the replicative capacities of the mutants were analyzed.@@@@1@41@@oe@16-12-2010 862779103@GENIA Treebank@formal@@1@S@All mutants, including one extensively mutagenized strain entirely missing the NF-kappaB and four Spl binding elements, replicated with wild-type kinetics and to a wild-type level in peripheral blood mononuclear cell cultures in 50 to 100% of the experiments.@@@@1@42@@oe@16-12-2010 862779104@GENIA Treebank@formal@@1@S@One group of mutants replicated very similarly to SIVmac239 in kinetics and yield in CEMxl74 cells (2xNFKappaB > or = SlVmac239 approximately deltaNFkappaB approximately deltaSpl234 approximately substNFkappaB approximately substSpl2 approximately substSp23), while a second group replicated with delayed or slightly delayed kinetics in CEMxl74 cells (SIVmac239 > substSp34 > deltaNFkappaBdeltaSpl234 approximately deltaNFkappaBdeltaSp1 > substSpl234).@@@@1@62@@oe@16-12-2010 862779105@GENIA Treebank@formal@@1@S@Reversions or additional mutations were not detected in the U3 and R regions of proviral DNA from CEMxl74 cells infected with the SIVmac239 mutants.@@@@1@25@@oe@16-12-2010 862779106@GENIA Treebank@formal@@1@S@Similar results were obtained when mutants of SIVmacMER (a macrophage-competent derivative of SIVmac239) were tested in peripheral blood mononuclear cell and CEMx174 cultures.@@@@1@26@@oe@16-12-2010 862779107@GENIA Treebank@formal@@1@S@However, the growth of most mutated viruses was suppressed in primary rhesus monkey alveolar macrophages (SIVmacMER approximately 2xNFkappaB approximately substNFkappaB > deltaNFkappaB > deltaNFkappaBdeltaSpl234 approximately deltaNFkappaBdeltaSpl > deltaSpl234 approximately substSpl2 > substSp23 approximately substSp34 approximately substSpl234 > or = SIVmac239).@@@@1@44@@oe@16-12-2010 862779108@GENIA Treebank@formal@@1@S@Thus, changes in the Sp1 binding sites had the most dramatic effects on SIVmac replication in primary macrophage cultures.@@@@1@21@@oe@16-12-2010 862779109@GENIA Treebank@formal@@1@S@Analysis of long terminal repeat-driven secreted alkaline phosphatase activity in transient assays showed that, unlike human immunodeficiency virus type 1, the SIV long terminal repeat possesses an enhancer region just upstream of the NF-kappaB element which maintains significant levels of basal transcription in the absence of NF-kappaB and Sp1 sites.@@@@1@53@@oe@16-12-2010 862779110@GENIA Treebank@formal@@1@S@This region is responsive to transactivation by Tat.@@@@1@9@@oe@16-12-2010 862779111@GENIA Treebank@formal@@1@S@In addition, the SIV TATA box was shown to be stronger than that of human immunodeficiency virus type 1.@@@@1@21@@oe@16-12-2010 862779112@GENIA Treebank@formal@@1@S@Therefore, the surprisingly high replicative capacity of NF-kappaB and Sp1 binding site mutants of SIVmac is due to unique features or the enhancer/promoter region.@@@@1@26@@oe@16-12-2010 862827401@GENIA Treebank@formal@@1@S@Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1: a potential mechanism for constitutive induction of NF-kappaB.@@@@1@24@@oe@16-12-2010 862827402@GENIA Treebank@formal@@1@S@In resting T lymphocytes, the transcription factor NF-kappaB is sequestered in the cytoplasm via interactions with members of the I kappa B family of inhibitors, including IkappaBalpha and IkappaBbeta.@@@@1@32@@oe@16-12-2010 862827403@GENIA Treebank@formal@@1@S@During normal T-cell activation, IkappaBalpha is rapidly phosphorylated, ubiquitinated, and degraded by the 26S proteasome, thus permitting the release of functional NF-kappaB.@@@@1@27@@oe@16-12-2010 862827404@GENIA Treebank@formal@@1@S@In contrast to its transient pattern of nuclear induction during an immune response, NF-kappaB is constitutively activated in cells expressing the Tax transforming protein of human T-cell leukemia virus type I (HTLV-1).@@@@1@36@@oe@16-12-2010 862827405@GENIA Treebank@formal@@1@S@Recent studies indicate that HTLV-1 Tax targets IkappaBalpha to the ubiquitin-proteasome pathway.@@@@1@13@@oe@16-12-2010 862827406@GENIA Treebank@formal@@1@S@However, it remains unclear how this viral protein induces a persistent rather than transient NF-kappaB response.@@@@1@18@@oe@16-12-2010 862827407@GENIA Treebank@formal@@1@S@In this report, we provide evidence that in addition to acting on IkappaBalpha, Tax stimulates the turnover Of IkappaBbeta via a related targeting mechanism.@@@@1@27@@oe@16-12-2010 862827408@GENIA Treebank@formal@@1@S@Like IkappaBalpha, Tax-mediated breakdown of IkappaBbeta in transfected T lymphocytes is blocked either by cell-permeable proteasome inhibitors or by mutation Of IkappaBbeta at two serine residues present within its N-terminal region.@@@@1@33@@oe@16-12-2010 862827409@GENIA Treebank@formal@@1@S@Despite the dual specificity of HTLV-1 Tax for IkappaBalpha and IkappaBbeta at the protein level, Tax selectively stimulates NF-kappaB-directed transcription of the IkappaBalpha gene.@@@@1@26@@oe@16-12-2010 862827410@GENIA Treebank@formal@@1@S@Consequently, IkappaBbeta protein expression is chronically downregulated in HTLV-1-infected T lymphocytes.@@@@1@13@@oe@16-12-2010 862827411@GENIA Treebank@formal@@1@S@These findings with IkappaBbeta provide a potential mechanism for the constitutive activation of NF-kappaB in Tax-expressing cells.@@@@1@18@@oe@16-12-2010 862828401@GENIA Treebank@formal@@1@S@Genetic characterization of transactivation of the human T-cell leukemia virus type 1 promoter: Binding of Tax to Tax-responsive element 1 is mediated by the cyclic AMP-responsive members of the CREB/ATF family of transcription factors.@@@@1@36@@oe@16-12-2010 862828402@GENIA Treebank@formal@@1@S@To achieve a better understanding of the mechanism of transactivation by Tax of human T-cell leukemia virus type 1 Tax-responsive element 1 (TRE-1), we developed a genetic approach with Saccharomyces cerevisiae.@@@@1@35@@oe@16-12-2010 862828403@GENIA Treebank@formal@@1@S@We constructed a yeast reporter strain containing the lacZ gene under the control of the CYC1 promoter associated with three copies of TRE-1.@@@@1@24@@oe@16-12-2010 862828404@GENIA Treebank@formal@@1@S@Expression of either the cyclic AMP response element-binding protein (CREB) or CREB fused to the GAL4 activation domain (GAD) in this strain did not modify the expression of the reporter gene.@@@@1@36@@oe@16-12-2010 862828405@GENIA Treebank@formal@@1@S@Tax alone was also inactive.@@@@1@6@@oe@16-12-2010 862828406@GENIA Treebank@formal@@1@S@However, expression of the reporter gene was induced by coexpression of Tax and CREB.@@@@1@16@@oe@16-12-2010 862828407@GENIA Treebank@formal@@1@S@This effect was stronger with the GAD-CREB fusion protein.@@@@1@10@@oe@16-12-2010 862828408@GENIA Treebank@formal@@1@S@Analysis of different CREB mutants with this genetic system indicated that the C-terminal 92 amino acid residues, which include the basic domain and the leucine zipper, are necessary and sufficient to mediate transactivation by Tax.@@@@1@38@@oe@16-12-2010 862828409@GENIA Treebank@formal@@1@S@To identify cellular proteins binding to TRE-1 in a Tax-dependent manner, this strain was also used to screen a library of human cDNAs fused to GAD.@@@@1@28@@oe@16-12-2010 862828410@GENIA Treebank@formal@@1@S@Of five positive clones isolated from 0.75 x 10(6) yeast colonies, four were members of the CREB/activating transcription factor (ATF) family: CREB, two isoforms of the cyclic AMP-responsive element modulator (CREM), and ATF-1.@@@@1@42@@oe@16-12-2010 862828411@GENIA Treebank@formal@@1@S@Interestingly, these three proteins can be phosphorylated by protein kinase A and thus form a particular subgroup within the CREB/ATF family.@@@@1@23@@oe@16-12-2010 862828412@GENIA Treebank@formal@@1@S@Expression of ATF-2 in S. cerevisiae did not activate TRE-1 in the presence of Tax.@@@@1@16@@oe@16-12-2010 862828413@GENIA Treebank@formal@@1@S@This shows that in a eukaryotic nucleus, Tax specifically interacts with the basic domain-leucine zipper region of ATF-1, CREB, and CREM.@@@@1@25@@oe@16-12-2010 862828414@GENIA Treebank@formal@@1@S@The fifth clone identified in this screening corresponded to the Ku autoantigen p70 subunit.@@@@1@15@@oe@16-12-2010 862828415@GENIA Treebank@formal@@1@S@When fused to GAD, the C-terminal region of Ku was able to activate transcription via TRE-1 but this activation was not dependent on Tax.@@@@1@26@@oe@16-12-2010 862829501@GENIA Treebank@formal@@1@S@Role of EGR1 in regulation of stimulus-dependent CD44 transcription in B lymphocytes.@@@@1@13@@oe@16-12-2010 862829502@GENIA Treebank@formal@@1@S@The immediate-early gene egr-1 encodes a transcription factor (EGR1) that links B-cell antigen receptor (BCR) signals to downstream activation events through the regulation of previously unidentified target genes.@@@@1@33@@oe@16-12-2010 862829503@GENIA Treebank@formal@@1@S@Here we identify the gene encoding the lymphocyte homing and migration protein CD44 as a target of EGR1 regulation in B cells.@@@@1@23@@oe@16-12-2010 862829504@GENIA Treebank@formal@@1@S@BCR-induced increases in CD44 mRNA expression and transcription levels are shown to occur in EGR1-expressing but not in nonexpressing subclones of the B-cell line WEHI-231.@@@@1@26@@oe@16-12-2010 862829505@GENIA Treebank@formal@@1@S@Kinetics of egr-1 transcription and the appearance of nuclear EGR1 protein precede CD44 induction and occur within 30 min after stimulation in the EGR1-expressing subclone.@@@@1@26@@oe@16-12-2010 862829506@GENIA Treebank@formal@@1@S@A single EGR1 binding motif is demonstrated at bp -301 of the human CD44 promoter.@@@@1@16@@oe@16-12-2010 862829507@GENIA Treebank@formal@@1@S@Cotransfection of a CD44 promoter-chloramphenicol acetyltransferase reporter construct with an egr-1 expression vector resulted in a 6.5- to 8.5-fold induction of transcriptional activity relative to an empty expression vector.@@@@1@30@@oe@16-12-2010 862829508@GENIA Treebank@formal@@1@S@The EGR1 binding motif was shown to be necessary for stimulus-induced expression of a CD44 promoter-chloramphenicol acetyltransferase reporter construct in nontransformed B lymphocytes and was required for transactivation by an EGR1 expression vector in a B-cell line.@@@@1@38@@oe@16-12-2010 862829509@GENIA Treebank@formal@@1@S@These studies identify EGR1 as an intermediary linking BCR-derived signals to the induction of CD44.@@@@1@16@@oe@16-12-2010 862829510@GENIA Treebank@formal@@1@S@The relevance of these molecular events to BCR signal transduction and antigen-stimulated B-cell-mediated immune responses is discussed.@@@@1@18@@oe@16-12-2010 862830601@GENIA Treebank@formal@@1@S@Identification of an inducible regulator of c-myb expression during T-cell activation.@@@@1@12@@oe@16-12-2010 862830602@GENIA Treebank@formal@@1@S@Resting T cells express very low levels of c-Myb protein.@@@@1@11@@oe@16-12-2010 862830603@GENIA Treebank@formal@@1@S@During T-cell activation, c-myb expression is induced and much of the increase in expression occurs at the transcriptional level.@@@@1@21@@oe@16-12-2010 862830604@GENIA Treebank@formal@@1@S@We identified a region of the c-myb 5' flanking sequence that increased c-myb expression during T-cell activation.@@@@1@18@@oe@16-12-2010 862830605@GENIA Treebank@formal@@1@S@In vivo footprinting by ligation-mediated PCR was performed to correlate in vivo protein binding with functional activity.@@@@1@18@@oe@16-12-2010 862830606@GENIA Treebank@formal@@1@S@A protein footprint was visible over this region of the c-myb 5' flanking sequence in activated T cells but not in unactivated T cells.@@@@1@25@@oe@16-12-2010 862830607@GENIA Treebank@formal@@1@S@An electrophoretic mobility shift assay (EMSA) with nuclear extract from activated T cells and an oligonucleotide of this binding site demonstrated a new protein-DNA complex, referred to as CMAT for c-myb in activated T cells; this complex was not present in unactivated T cells.@@@@1@49@@oe@16-12-2010 862830608@GENIA Treebank@formal@@1@S@Because the binding site showed some sequence similarity with the nuclear factor of activated T cells (NFAT) binding site, we compared the kinetics of induction of the two binding complexes and the molecular masses of the two proteins.@@@@1@42@@oe@16-12-2010 862830609@GENIA Treebank@formal@@1@S@Studies of the kinetics of induction showed that the NFAT EMSA binding complex appeared earlier than the CMAT complex.@@@@1@20@@oe@16-12-2010 862830610@GENIA Treebank@formal@@1@S@The NFAT protein migrated more slowly in a sodium dodecyl sulfate-polyacrylamide gel than the CMAT protein did.@@@@1@18@@oe@16-12-2010 862830611@GENIA Treebank@formal@@1@S@In addition, an antibody against NFAT did not cross-react with the CMAT protein.@@@@1@15@@oe@16-12-2010 862830612@GENIA Treebank@formal@@1@S@The appearance of the CMAT binding complex was inhibited by both cyclosporin A and rapamycin.@@@@1@16@@oe@16-12-2010 862830613@GENIA Treebank@formal@@1@S@The CMAT protein appears to be a novel inducible protein involved in the regulation of c-myb expression during T-cell activation.@@@@1@21@@oe@16-12-2010 863180901@GENIA Treebank@formal@@1@S@Activation of nuclear factor of activated T cells in a cyclosporin A-resistant pathway.@@@@1@14@@oe@16-12-2010 863180902@GENIA Treebank@formal@@1@S@The mechanism of action of the immunosuppressive drug cyclosporin A (CsA) is the inactivation of the Ca2+/calmodulin-dependent serine-threonine phosphatase calcineurin by the drug-immunophilin complex.@@@@1@27@@oe@16-12-2010 863180903@GENIA Treebank@formal@@1@S@Inactive calcineurin is unable to activate the nuclear factor of activated T cells (NFAT), a transcription factor required for expression of the interleukin 2 (IL-2) gene.@@@@1@32@@oe@16-12-2010 863180904@GENIA Treebank@formal@@1@S@IL-2 production by CsA-treated cells is therefore dramatically reduced.@@@@1@10@@oe@16-12-2010 863180905@GENIA Treebank@formal@@1@S@We demonstrate here, however, that NFAT can be activated, and significant levels of IL-2 can be produced by the CsA-resistant CD28-signaling pathway.@@@@1@26@@oe@16-12-2010 863180906@GENIA Treebank@formal@@1@S@In transient transfection assays, both multicopy NFAT- and IL-2 promoter-beta-galactosidase reporter gene constructs could be activated by phorbol 12-myristate 13-acetate (PMA)/alpha-CD28 stimulation, and this activation was resistant to CsA.@@@@1@35@@oe@16-12-2010 863180907@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assay showed the induction of a CsA-resistant NFAT complex in the nuclear extracts of peripheral blood T cells stimulated with PMA plus alphaCD28.@@@@1@27@@oe@16-12-2010 863180908@GENIA Treebank@formal@@1@S@Peripheral blood T cells stimulated with PMA/alphaCD28 produced IL-2 in the presence of CsA.@@@@1@15@@oe@16-12-2010 863180909@GENIA Treebank@formal@@1@S@Collectively, these data suggest that NFAT can be activated and IL-2 can be produced in a calcineurin independent manner.@@@@1@21@@oe@16-12-2010 863182101@GENIA Treebank@formal@@1@S@Structural and functional characterization of the human CD36 gene promoter: identification of a proximal PEBP2/CBF site.@@@@1@18@@oe@16-12-2010 863182102@GENIA Treebank@formal@@1@S@CD36 is a cell surface glycoprotein composed of a single polypeptide chain, which interacts with thrombospondin, collagens type I and IV, oxidized low density lipoprotein, fatty acids, anionic phospholipids, and erythrocytes parasitized with Plasmodium falciparum.@@@@1@42@@oe@16-12-2010 863182103@GENIA Treebank@formal@@1@S@Its expression is restricted to a few cell types, including monocyte/macrophages.@@@@1@13@@oe@16-12-2010 863182104@GENIA Treebank@formal@@1@S@In these cells, CD36 is involved in phagocytosis of apoptotic cells, and foam cell formation by uptake of oxidized low density lipoprotein.@@@@1@25@@oe@16-12-2010 863182105@GENIA Treebank@formal@@1@S@To study the molecular mechanisms that control the transcription of the CD36 gene in monocytic cells we have isolated and analyzed the CD36 promoter.@@@@1@25@@oe@16-12-2010 863182106@GENIA Treebank@formal@@1@S@Transient expression experiments of 5'-deletion fragments of the CD36 promoter coupled to luciferase demonstrated that as few as 158 base pairs upstream from the transcription initiation site were sufficient to direct the monocyte-specific transcription of the reporter gene.@@@@1@39@@oe@16-12-2010 863182107@GENIA Treebank@formal@@1@S@Within the above region, the fragment spanning nucleotides -158 to -90 was required for optimal transcription in monocytic cells.@@@@1@21@@oe@16-12-2010 863182108@GENIA Treebank@formal@@1@S@Biochemical analysis of the region -158/-90 revealed a binding site for transcription factors of the polyomavirus enhancer-binding protein 2/core-binding factor (PEBP2/CBF) family at position -103.@@@@1@28@@oe@16-12-2010 863182109@GENIA Treebank@formal@@1@S@Disruption of the PEBP2/CBF site markedly diminished the role of the PEBP2/CBF factors in the constitutive transcription of the CD36 gene.@@@@1@22@@oe@16-12-2010 863182110@GENIA Treebank@formal@@1@S@The involvement of members of the PEBP2/CBF family in chromosome translocations associated with acute myeloid leukemia, and in the transcriptional regulation of the myeloid-specific genes encoding for myeloperoxidase, elastase, and the colony-stimulating factor receptor, highlights the relevance of the regulation of the CD36 gene promoter in monocytic cells by members of the PEBP2/CBF family.@@@@1@59@@oe@16-12-2010 863196201@GENIA Treebank@formal@@1@S@Granulocyte-macrophage colony-stimulating factor stimulates JAK2 signaling pathway and rapidly activates p93fes, STAT1 p91, and STAT3 p92 in polymorphonuclear leukocytes.@@@@1@22@@oe@16-12-2010 863196202@GENIA Treebank@formal@@1@S@Granulocyte-macrophage colony-stimulating factor (GM-CSF), supports proliferation, differentiation, and functional activation of hemopoietic cells by its interaction with a heterodimeric receptor.@@@@1@26@@oe@16-12-2010 863196203@GENIA Treebank@formal@@1@S@Although GM-CSF receptor is devoid of tyrosine kinase enzymatic activity, GM-CSF-induced peripheral blood polymorphonuclear leukocytes (PMN) functional activation is mediated by the phosphorylation of a large number of intracellular signaling molecules.@@@@1@35@@oe@16-12-2010 863196204@GENIA Treebank@formal@@1@S@We have previously shown that JAK2 becomes tyrosine-phosphorylated in response to GM-CSF in PMN.@@@@1@15@@oe@16-12-2010 863196205@GENIA Treebank@formal@@1@S@In the present study we demonstrate that also the signal transducers and activators of transcription (STAT) family members STAT1 p91 and STAT3 p92 and the product of the c-fps/fes protooncogene become tyrosine-phosphorylated upon GM-CSF stimulation and physically associated with both GM-CSF receptor beta common subunit and JAK2.@@@@1@50@@oe@16-12-2010 863196206@GENIA Treebank@formal@@1@S@Moreover GM-CSF was able to induce JAK2 and p93fes catalytic activity.@@@@1@12@@oe@16-12-2010 863196207@GENIA Treebank@formal@@1@S@We also demonstrate that the association of the GM-CSF receptor beta common subunit with JAK2 is ligand-dependent.@@@@1@18@@oe@16-12-2010 863196208@GENIA Treebank@formal@@1@S@Finally we demonstrate that GM-CSF induces a DNA-binding complex that contains both p91 and p92.@@@@1@16@@oe@16-12-2010 863196209@GENIA Treebank@formal@@1@S@These results identify a new signal transduction pathway activated by GM-CSF and provide a mechanism for rapid activation of gene expression in GM-CSF-stimulated PMN.@@@@1@25@@oe@16-12-2010 863267001@GENIA Treebank@formal@@1@S@Expression of Id2 and Id3 mRNA in human lymphocytes.@@@@1@10@@oe@16-12-2010 863267002@GENIA Treebank@formal@@1@S@Helix-loop-helix (HLH) transcription factors are involved in cellular growth and differentiation.@@@@1@14@@oe@16-12-2010 863267003@GENIA Treebank@formal@@1@S@The Id (inhibitor of DNA binding and differentiation) HLH proteins, in a dominantly negative fashion, regulate transcriptional activities of basic HLH proteins.@@@@1@27@@oe@16-12-2010 863267004@GENIA Treebank@formal@@1@S@We examined by northern hybridization the expression of Id2 and Id3 mRNA in human leukemia/lymphoma lines and patient samples, as well as resting and activated normal human lymphocytes from peripheral blood (PBL).@@@@1@36@@oe@16-12-2010 863267005@GENIA Treebank@formal@@1@S@The Id2 mRNA was abundantly expressed in 5/12 T-cell and 3/4 B-cell lines, and Id3 mRNA was detected in 4/12 T-cell and 3/4 B-cell lines.@@@@1@27@@oe@16-12-2010 863267006@GENIA Treebank@formal@@1@S@Interestingly, Id2, but not Id3, mRNA was strongly expressed in 4/5 T-cell lines infected with human T-cell leukemia virus type I (HTLV-I) (ATL-1k, MT-2, S-LB1) and type II (Mo).@@@@1@41@@oe@16-12-2010 863267007@GENIA Treebank@formal@@1@S@Another unexpected finding was that T-cell leukemias and T-cell lines often expressed either Id2 or Id3 mRNA.@@@@1@18@@oe@16-12-2010 863267008@GENIA Treebank@formal@@1@S@In addition, resting PBL constitutively expressed prominent levels of Id2 mRNA, but not Id3 mRNA.@@@@1@18@@oe@16-12-2010 863267009@GENIA Treebank@formal@@1@S@Upon PHA-stimulation, Id2 expression decreased and Id3 levels increased with biphasic kinetics.@@@@1@14@@oe@16-12-2010 863267010@GENIA Treebank@formal@@1@S@Taken together, our studies revealed three unexpected findings which require further analysis: (1) expression of Id2 mRNA is often associated with lymphocytic transformation by HTLV-I or -II; (2) T-cells usually express either Id2 or Id3 mRNA, but B-cells often express both simultaneously; (3) non-dividing, normal PBL express high levels of Id2 and no Id3 mRNA; and with the onset of cellular proliferation, levels of Id2 mRNA decrease while levels of Id3 mRNA increase, suggesting that regulation of expression of these closely related genes is disparate.@@@@1@101@@oe@16-12-2010 863299901@GENIA Treebank@formal@@1@S@CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency.@@@@1@12@@oe@16-12-2010 863299902@GENIA Treebank@formal@@1@S@Tumor necrosis factor (TNF) mediates a wide variety of disease states including septic shock, acute and chronic inflammation, and cachexia.@@@@1@25@@oe@16-12-2010 863299903@GENIA Treebank@formal@@1@S@Recently, a multivalent guanylhydrazone (CNI-1493) developed as an inhibitor of macrophage activation was shown to suppress TNF production and protect against tissue inflammation and endotoxin lethality [Bianchi, M., Ulrich, P., Bloom, O., Meistrell, M., Zimmerman, G.A., Schmidtmayerova, H., Bukrinsky, M., Donnelley, T., Bucala, R., Sherry, B., Manogue, K.R., Tortolani, A.J., Cerami, A.& Tracey, K.J.(1995) Mol.Med.1, 254-266, and Bianchi, M., Bloom, O., Raabe, T., Cohen, P. S., Chesney, J., Sherry, B., Schmidtmayerova, H., Zhang, X., Bukrinsky, M., Ulrich, P., Cerami, A.& Tracey, J.(1996) J.Exp.Med., in press].@@@@1@150@@oe@16-12-2010 863299904@GENIA Treebank@formal@@1@S@We have now elucidated the mechanism by which CNI-1493 inhibits macrophage TNF synthesis and show here that it acts through suppression of TNF translation efficiency.@@@@1@26@@oe@16-12-2010 863299905@GENIA Treebank@formal@@1@S@CNI-1493 blocked neither the lipopolysaccharide (LPS)-induced increases in the expression of TNF mRNA nor the translocation of nuclear factor NF-kappa B to the nucleus in macrophages activated by 15 min of LPS stimulation, indicating that CNI-1493 does not interfere with early NF-kappa B-mediated transcriptional regulation of TNF.@@@@1@52@@oe@16-12-2010 863299906@GENIA Treebank@formal@@1@S@However, synthesis of the 26-kDa membrane form of TNF was effectively blocked by CNI-1493.@@@@1@16@@oe@16-12-2010 863299907@GENIA Treebank@formal@@1@S@Further evidence for the translational suppression of TNF is given by experiments using chloram-phenicol acetyltransferase (CAT) constructs containing elements of the TNF gene that are involved in TNF translational regulation.@@@@1@33@@oe@16-12-2010 863299908@GENIA Treebank@formal@@1@S@Both the 5' and 3' untranslated regions of the TNF gene were required to elicit maximal translational suppression by CNI-1493.@@@@1@21@@oe@16-12-2010 863299909@GENIA Treebank@formal@@1@S@Identification of the molecular target through which CNI- 1493 inhibits TNF translation should provide insight into the regulation of macrophage activation and mechanisms of inflammation.@@@@1@25@@oe@16-12-2010 863441301@GENIA Treebank@formal@@1@S@STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients.@@@@1@15@@oe@16-12-2010 863441302@GENIA Treebank@formal@@1@S@A signal transduction pathway activated by many cytokines has recently been elaborated.@@@@1@13@@oe@16-12-2010 863441303@GENIA Treebank@formal@@1@S@The JAK kinases and the signal transducers and activators of transcription (STAT) factors have been found to be essential components.@@@@1@23@@oe@16-12-2010 863441304@GENIA Treebank@formal@@1@S@In this report, we describe the presence of constitutively activated STAT factors in peripheral blood cells from patients with acute leukemia.@@@@1@23@@oe@16-12-2010 863441305@GENIA Treebank@formal@@1@S@We used oligonucleotide probes from the beta-casein and IRF-1 gene promoters and the ISRE probe to detect STAT proteins in nuclear extracts from acute leukemia cells in bandshift assays.@@@@1@30@@oe@16-12-2010 863441306@GENIA Treebank@formal@@1@S@Specific DNA protein complex formation was observed with the probes from the beta-casein and IRF-1 gene promoters, but not with the ISRE oligonucleotide probe, when cell extracts from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were investigated.@@@@1@46@@oe@16-12-2010 863441307@GENIA Treebank@formal@@1@S@We used nonradioactive oligonucleotides as competitors to show the specificity of the complex formation.@@@@1@15@@oe@16-12-2010 863441308@GENIA Treebank@formal@@1@S@Specific antibodies directed against the individual STAT proteins were used in supershift experiments.@@@@1@14@@oe@16-12-2010 863441309@GENIA Treebank@formal@@1@S@STAT5- and STAT1-related factors were detected in ALL and STAT1-, STAT3-, and STAT5-related proteins were present in nuclear cell extracts from AML.@@@@1@25@@oe@16-12-2010 863441310@GENIA Treebank@formal@@1@S@Since the cells were not treated with cytokines before the nuclear proteins were extracted, we conclude that these factors are constitutively activated in vivo.@@@@1@26@@oe@16-12-2010 863441311@GENIA Treebank@formal@@1@S@It is likely that the constitutive activation of STAT proteins is a part of the events of leukemogenesis.@@@@1@19@@oe@16-12-2010 863441801@GENIA Treebank@formal@@1@S@The RAR-RXR as well as the RXR-RXR pathway is involved in signaling growth inhibition of human CD34+ erythroid progenitor cells.@@@@1@21@@oe@16-12-2010 863441802@GENIA Treebank@formal@@1@S@Previous studies have shown that retinoic acid (RA), similar to tumor necrosis factor-alpha (TNF-alpha), can act as a bifunctional regulator of the growth of bone marrow progenitors, in that it can stimulate granulocyte-macrophage colony-stimulating factor (GM-CSF)- or interleukin-3 (IL-3)-induced GM colony formation, but potently inhibit G-CSF-induced growth.@@@@1@62@@oe@16-12-2010 863441803@GENIA Treebank@formal@@1@S@The present study, using highly enriched human CD34+ as well as Lin- murine bone marrow progenitor cells, demonstrates a potent inhibitory effect of 9-cis-RA on burst-forming unit-erythroid (BFU-E) colony formation regardless of the cytokine stimulating growth.@@@@1@41@@oe@16-12-2010 863441804@GENIA Treebank@formal@@1@S@Specifically, 9-cis-RA potently inhibited the growth of BFU-E response to erythropoietin (Epo) (100%), stem cell factor (SCF) + Epo (92%), IL-3 + Epo (97%), IL-4 + Epo (88%), and IL-9 + Epo (100%).@@@@1@58@@oe@16-12-2010 863441805@GENIA Treebank@formal@@1@S@Erythroid colony growth was also inhibited when CD34+ progenitors were seeded at one cell per well, suggesting a direct action of RA.@@@@1@24@@oe@16-12-2010 863441806@GENIA Treebank@formal@@1@S@Using synthetic ligands to retinoic acid receptors (RARs) and retinoid X receptors (RXRs) that selectively bind and activate RAR-RXR or RXR-RXR dimers, respectively, we dissected the involvement of the two retinoid response pathways in the regulation of normal myeloid and erythroid progenitor cell growth.@@@@1@51@@oe@16-12-2010 863441807@GENIA Treebank@formal@@1@S@Transactivation studies showed that both the RAR (Ro 13-7410) and RXR (Ro 25-6603 and Ro 25-7386) ligands were highly selective at 100 nmol/L.@@@@1@28@@oe@16-12-2010 863441808@GENIA Treebank@formal@@1@S@At this concentration, Ro 13-7410 potently inhibited G-CSF-stimulated myeloid as well as SCF + Epo-induced erythroid colony growth.@@@@1@20@@oe@16-12-2010 863441809@GENIA Treebank@formal@@1@S@At the same concentration, Ro 25-6603 and Ro 25-7386 had little or no effect on G-CSF-induced colony formation, whereas they inhibited 75% and 53%, respectively, of SCF + Epo-stimulated BFU-E colony growth.@@@@1@39@@oe@16-12-2010 863441810@GENIA Treebank@formal@@1@S@Thus, the RAR-RXR response pathway can signal growth inhibition of normal bone marrow myeloid and erythroid progenitor cells.@@@@1@20@@oe@16-12-2010 863441811@GENIA Treebank@formal@@1@S@In addition, we demonstrate a unique involvement of the RXR-RXR pathway in mediating growth inhibition of erythroid but not myeloid progenitor cells.@@@@1@24@@oe@16-12-2010 863443801@GENIA Treebank@formal@@1@S@Expression of A-myb, but not c-myb and B-myb, is restricted to Burkitt's lymphoma, sIg+ B-acute lymphoblastic leukemia, and a subset of chronic lymphocytic leukemias.@@@@1@30@@oe@16-12-2010 863443802@GENIA Treebank@formal@@1@S@The A-myb gene encodes a transcription factor that is related both functionally and structurally to the v-myb oncogene.@@@@1@19@@oe@16-12-2010 863443803@GENIA Treebank@formal@@1@S@Following our observations that A-myb is expressed in a restricted subset of normal mature human B lymphocytes, with the phenotype CD38+, CD39-, slgM-, we have now investigated the pattern of A-myb expression in neoplastic B cells representating the whole spectrum of B-cell differentiation and compared it to that of c-myb and B-myb.@@@@1@57@@oe@16-12-2010 863443804@GENIA Treebank@formal@@1@S@In a panel of 32 B-cell lines, A-myb was very strongly expressed in most Burkitt's lymphoma (BL) cell lines, but weak or negative in 2 pre-B acute lymphoblastic leukemia (ALL), 4 non-Hodgkin's lymphoma (NHL), 6 Epstein-Barr virus-immortalized lymphoblastoid cell lines, and 6 myeloma lines.@@@@1@58@@oe@16-12-2010 863443805@GENIA Treebank@formal@@1@S@Protein expression paralleled that of the RNA.@@@@1@8@@oe@16-12-2010 863443806@GENIA Treebank@formal@@1@S@We have also investigated A-myb expression in 49 fresh cases of B leukemias.@@@@1@14@@oe@16-12-2010 863443807@GENIA Treebank@formal@@1@S@Among 24 ALL, 6 were of the null and 11 of the common type and all these were negative for A-myb expression; on the other hand, all 7 B-ALL cases (slg+), as well as one fresh BL case with bone marrow infiltration, expressed A-myb.@@@@1@52@@oe@16-12-2010 863443808@GENIA Treebank@formal@@1@S@A-myb was undetectable in 4 prolymphocytic leukemias (PLL) but was strongly expressed in 5/20 (25%) of chronic lymphocytic leukemia (CLL) samples.@@@@1@29@@oe@16-12-2010 863443809@GENIA Treebank@formal@@1@S@In the latter A-myb did not correlate with phenotype or clinical stage.@@@@1@13@@oe@16-12-2010 863443810@GENIA Treebank@formal@@1@S@Finally, we have studied the progression of one case of CLL into Richter's syndrome and have found that the Richter's cells expressed about 25-fold less A-myb RNA than the CLL cells from the same patient.@@@@1@39@@oe@16-12-2010 863443811@GENIA Treebank@formal@@1@S@The pattern of c-myb and B-myb was clearly distinct from that of A-myb.@@@@1@14@@oe@16-12-2010 863443812@GENIA Treebank@formal@@1@S@C-myb and B-myb were expressed in all neoplastic groups, except in CLL cells.@@@@1@15@@oe@16-12-2010 863443813@GENIA Treebank@formal@@1@S@Thus, A-myb expression, unlike that of c-myb and B-myb, is restricted to a subset of B-cell neoplasias (in particular BL and slg+B-ALL) representative of a specific stage of B-cell differentiation.@@@@1@36@@oe@16-12-2010 863443814@GENIA Treebank@formal@@1@S@This expression may in part reflect expression of A-myb by the normal germinal center B cells that are the normal counterpart of these transformed B cells.@@@@1@27@@oe@16-12-2010 863443815@GENIA Treebank@formal@@1@S@The data presented strongly support a role for this transcription factor in B-cell differentiation and perhaps in B-cell transformation in some neoplasias.@@@@1@23@@oe@16-12-2010 863444001@GENIA Treebank@formal@@1@S@Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations.@@@@1@13@@oe@16-12-2010 863444002@GENIA Treebank@formal@@1@S@T-cell prolymphocytic leukemia (T-PLL), a rare form of mature T-cell leukemias, and ataxia telangiectasia clonal proliferation, a related condition occurring in patients suffering from ataxia telangiectasia, have been associated to translocations involving the 14q32.1 or Xq28 regions, where are located the TCL1 and MTCP1 putative oncogenes, respectively.@@@@1@56@@oe@16-12-2010 863444003@GENIA Treebank@formal@@1@S@The MTCP1 gene is involved in the t(X;14)(q28;q11) translocation associated with these T-cell proliferations.@@@@1@15@@oe@16-12-2010 863444004@GENIA Treebank@formal@@1@S@Alternative splicing generates type A and B transcripts that potentially encode two entirely distinct proteins; type A transcripts code for a small mitochondrial protein, p8MTCP1, and type B transcripts, containing an additional open reading frame, may code for 107 amino-acid protein, p13MTCP1.@@@@1@49@@oe@16-12-2010 863444005@GENIA Treebank@formal@@1@S@The recently cloned TCL1 gene, also involved in translocations and inversions associated with T-cell proliferations, codes for a 14-kD protein that displays significant homology with p13MTCP1.@@@@1@29@@oe@16-12-2010 863444006@GENIA Treebank@formal@@1@S@We have generated rabbit antisera against this putative p13MTCP1 protein and screened for expression of p13MTCP1 normal lymphoid tissues and 33 cases of immature and mature lymphoid T-cell proliferations using a sensitive Western blot assay.@@@@1@36@@oe@16-12-2010 863444007@GENIA Treebank@formal@@1@S@We also investigated the MTCP1 locus configuration by Southern blot analysis.@@@@1@12@@oe@16-12-2010 863444008@GENIA Treebank@formal@@1@S@The p13MTCP1 protein was detected in the three T-cell proliferations with MTCP1 rearrangements because of t(X;14) translocations, but neither in normal resting and activated lymphocytes nor in the other T-cell leukemias.@@@@1@33@@oe@16-12-2010 863444009@GENIA Treebank@formal@@1@S@Our data support the hypothesis that p13MTCP1 and p14TCL1 form a new protein family that plays a key role in the pathogenesis of T-PLL and related conditions.@@@@1@28@@oe@16-12-2010 863552301@GENIA Treebank@formal@@1@S@Reversible differentiation of human monoblastic leukemia U937 cells by ML-9, an inhibitor of myosin light chain kinase.@@@@1@19@@oe@16-12-2010 863552302@GENIA Treebank@formal@@1@S@Human monoblastic leukemia U937 cells are induced to differentiate into monocytes and macrophages by various agents.@@@@1@17@@oe@16-12-2010 863552303@GENIA Treebank@formal@@1@S@We have shown that 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-9), an inhibitor of myosin light chain kinase, induces differentiation of monocytoid leukemia cell lines U937 and THP-1 but not of myeloblastic leukemic ML-1 cell or erythroleukemia K562 cells.@@@@1@40@@oe@16-12-2010 863552304@GENIA Treebank@formal@@1@S@In the present study, we further analyzed the effect of ML-9 in comparison with that of 1 alpha, 25-dihydroxyvitamin D3 (VD3) a typical inducer of monocytic differentiation.@@@@1@30@@oe@16-12-2010 863552305@GENIA Treebank@formal@@1@S@ML-9 induced nitroblue tetrazolium (NBT)-reducing activity of U937 cell more rapidly than VD3: This differentiation marker was induced significantly after incubation with ML-9 and VD3 for 4 hours and 1 day, respectively.@@@@1@38@@oe@16-12-2010 863552306@GENIA Treebank@formal@@1@S@ML-9 also induced alpha-naphthyl acetate esterase (ANAE) activity, another monocytic differentiation marker, more rapidly than VD3.@@@@1@21@@oe@16-12-2010 863552307@GENIA Treebank@formal@@1@S@The maximum levels of these markers induced by ML-9 were comparable to those induced by VD3, but after removal of ML-9 from the medium by washing the cells, the expressions of theses markers decreased within 4 hours and reached basal levels in 1 day, indicating that ML-9's induction of expression of differentiation-associated phenotypes was reversible.@@@@1@60@@oe@16-12-2010 863552308@GENIA Treebank@formal@@1@S@The growth inhibition of U937 cells by ML-9 was also reversible.@@@@1@12@@oe@16-12-2010 863552309@GENIA Treebank@formal@@1@S@Similar effects were observed in another line of human monoblastic cells, THP-1.@@@@1@14@@oe@16-12-2010 863552310@GENIA Treebank@formal@@1@S@ML-9 had little or no effect on the morphology of U937 cells but increased the expression of monocyte-macrophage lineage-associated surface antigen, CD14, to some extent.@@@@1@28@@oe@16-12-2010 863552311@GENIA Treebank@formal@@1@S@Irreversible terminal differentiation induced by VD3 is associated with down regulation of the expression of c-myc and upregulation of the expression of c-fos and c-jun, but ML-9 did not affect the expression of these oncogenes appreciably.@@@@1@38@@oe@16-12-2010 863552312@GENIA Treebank@formal@@1@S@ML-9-induced differentiation was also reversible when the cells were cultured with cultured with ML-9 plus an anti-cancer drug such as 1-beta-D-arabino-furanosylcytosine or daunomycin.@@@@1@24@@oe@16-12-2010 863552313@GENIA Treebank@formal@@1@S@it became irreversible, however, upon simultaneous treatment with dexamethasone and transforming growth factor-beta 1 (TGF-beta 1), which did not induce differentiation of U937 cells but caused growth arrest of the cells in the G0/G1 phase of the cell cycle.@@@@1@45@@oe@16-12-2010 863552314@GENIA Treebank@formal@@1@S@These results suggest that ML-9 should be useful for studying the mechanisms of monocytic differentiation.@@@@1@16@@oe@16-12-2010 863946101@GENIA Treebank@formal@@1@S@Lymphoid cell resistance to glucocorticoids in HIV infection.@@@@1@9@@oe@16-12-2010 863946102@GENIA Treebank@formal@@1@S@In humans infected with the HIV-1 virus there may be a disproportionate severity of signs and symptoms of illness compared to the fraction of CD4+ infected T-lymphoid cells.@@@@1@29@@oe@16-12-2010 863946103@GENIA Treebank@formal@@1@S@In part, this may be due to altered intercellular signalling systems and intracellular signal transduction.@@@@1@17@@oe@16-12-2010 863946104@GENIA Treebank@formal@@1@S@Glucocorticoids are well known for their effects on the vitality and function of lymphoid cells.@@@@1@16@@oe@16-12-2010 863946105@GENIA Treebank@formal@@1@S@Patients with HIV infections often show elevated circulating levels of cortisol, suggesting some misfunction in the regulatory systems that maintain the levels of this critical hormone.@@@@1@28@@oe@16-12-2010 863946106@GENIA Treebank@formal@@1@S@At the cellular level, it is known that both acute HIV infection and glucocorticoids can cause apoptotic cell death in thymic lymphocytes.@@@@1@24@@oe@16-12-2010 863946107@GENIA Treebank@formal@@1@S@However, chronically HIV-infected cells appear to be resistant to glucocorticoid-evoked cell death.@@@@1@14@@oe@16-12-2010 863946108@GENIA Treebank@formal@@1@S@Glucocorticoid receptor-ligand binding studies on patients' cells have shown reduced affinity between the receptor binding sites and test steroids.@@@@1@21@@oe@16-12-2010 863946109@GENIA Treebank@formal@@1@S@In vitro, chronically HIV-infected cells of the lymphoid CEM line displayed resistance to glucocorticoid-induced apoptosis.@@@@1@17@@oe@16-12-2010 863946110@GENIA Treebank@formal@@1@S@These cells showed reduced numbers of binding sites with little alteration in apparent affinity between ligand and receptor.@@@@1@19@@oe@16-12-2010 863946111@GENIA Treebank@formal@@1@S@Thus it appears that there may often be malfunction of the normal glucocorticoid response in HIV-infected cells probably due to altered interactions between the glucocorticoid receptor and its hormone.@@@@1@30@@oe@16-12-2010 863946112@GENIA Treebank@formal@@1@S@Such alterations may have clinical consequences, including the possibility of a relatively longer life span of infected CD4+ T-lymphocytes, as well as systemic effects of chronically elevated cortisol level.@@@@1@32@@oe@16-12-2010 864134601@GENIA Treebank@formal@@1@S@Interferon-gamma modulates the lipopolysaccharide-induced expression of AP-1 and NF-kappa B at the mRNA and protein level in human monocytes.@@@@1@20@@oe@16-12-2010 864134602@GENIA Treebank@formal@@1@S@Interferon-gamma (IFN-gamma) modulates the expression of several cytokines by human monocytes at the transcriptional level.@@@@1@18@@oe@16-12-2010 864134603@GENIA Treebank@formal@@1@S@In view of these findings, we analyzed the effects of IFN-gamma on the expression of different transcription factors in activated human monocytes.@@@@1@24@@oe@16-12-2010 864134604@GENIA Treebank@formal@@1@S@Priming of human monocytes with IFN-gamma resulted in the down regulation of c-fos and c-jun mRNA in response to stimulation with lipopolysaccharide (LPS) compared to the effects of LPS alone.@@@@1@33@@oe@16-12-2010 864134605@GENIA Treebank@formal@@1@S@Not only was this effect observed at the mRNA level, but activator protein-1 (AP-1) DNA binding capacity was affected as well, A strong reduction was observed in the LPS-induced DNA-binding activity of AP-1 in the presence of IFN-gamma.@@@@1@43@@oe@16-12-2010 864134606@GENIA Treebank@formal@@1@S@LPS-stimulated monocytes showed an increased expression of p105 mRNA, the precursor of the p50 subunit of the transcription factor nuclear factor-kappa B (NF-kappa B), while no effect was noticed on the expression of p65 mRNA.@@@@1@40@@oe@16-12-2010 864134607@GENIA Treebank@formal@@1@S@In contrast, IFN-gamma priming did not affect the expression of p105 transcripts but enhanced the expression of p65 mRNA (two-fold).@@@@1@24@@oe@16-12-2010 864134608@GENIA Treebank@formal@@1@S@Priming with IFN-gamma followed by LPS stimulation resulted in a further increase in the expression of p65 mRNA.@@@@1@19@@oe@16-12-2010 864134609@GENIA Treebank@formal@@1@S@This was due to an increase in the half-life of p65 mRNA (75 vs 150 minutes).@@@@1@19@@oe@16-12-2010 864134610@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift assays (EMSAs) demonstrated that unstimulated monocytes predominantly expressed p50 NF-kappa B.@@@@1@17@@oe@16-12-2010 864134611@GENIA Treebank@formal@@1@S@Stimulation with LPS or IFN-gamma resulted in the expression of p50 and p65 subunits, while the combination of IFN-gamma plus LPS caused a further increase in the expression of NF-kappa B.@@@@1@33@@oe@16-12-2010 864134612@GENIA Treebank@formal@@1@S@With Western blotting, it was shown that nuclear extracts from monocytes contained p50 and p65 protein in response to LPS and IFN-gamma stimulation.@@@@1@25@@oe@16-12-2010 864134613@GENIA Treebank@formal@@1@S@However, the combined stimulation did not result in enhanced p50 and p65 protein expression.@@@@1@16@@oe@16-12-2010 864134614@GENIA Treebank@formal@@1@S@The effects of IFN-gamma on the transcription factors were specific, since no change was observed in the expression of NF-IL-6 or I kappa B alpha, the inhibitor of NF-kappa B.@@@@1@33@@oe@16-12-2010 864134615@GENIA Treebank@formal@@1@S@We conclude that the effects of IFN-gamma on the expression of the transcription factors AP-1 and NF-kappa B may be important for the modulatory effects of IFN-gamma on the cytokine expression in activated human monocytes.@@@@1@36@@oe@16-12-2010 864135301@GENIA Treebank@formal@@1@S@Expression of c-fos and c-jun proteins and AP-1 binding activity during cell cycle progression of HL60 cells and phytohemagglutinin-stimulated lymphocytes.@@@@1@21@@oe@16-12-2010 864135302@GENIA Treebank@formal@@1@S@The protein products of the c-fos (p62c-fos) and c-jun (p39c-jun) genes are members of the AP-1 transcription factor family and are thought to play important roles in the regulation of gene expression during the cell cycle.@@@@1@41@@oe@16-12-2010 864135303@GENIA Treebank@formal@@1@S@Most studies on the expression of these proteins in relation to the cell cycle have been performed at the mRNA level, and therefore do not give direct information about the presence of the proteins during the cell cycle.@@@@1@40@@oe@16-12-2010 864135304@GENIA Treebank@formal@@1@S@We have used Western blotting to investigate the presence of these proteins during the cell cycles of two different cellular systems: a continuously growing myeloid leukemic cell line, HL60, and normal cells stimulated into cycle, phyto- hemagglutinin (PHA)-stimulated normal human peripheral blood lymphocytes (PBL).@@@@1@53@@oe@16-12-2010 864135305@GENIA Treebank@formal@@1@S@The binding activity of transcription factor AP-1, which consists of dimers of Fos and Jun family proteins, was also studied using a gel shift assay.@@@@1@28@@oe@16-12-2010 864135306@GENIA Treebank@formal@@1@S@We found nuclear p62c-fos, p39c-jun, and AP-1 binding activity throughout the cell cycle both in HL60 cells and in PHA-stimulated PBL, and we postulate that these proteins are required throughout the cell cycle and not transiently in the G0 to G1 transition as previous mRNA studies have indicated.@@@@1@52@@oe@16-12-2010 864135307@GENIA Treebank@formal@@1@S@We demonstrated an uncoupling of AP-1 binding activity from p62c-fos, and p39c-jun AP-1 activity was expressed more strongly in the G1- and G2/M-phase enriched samples than in the S-phase enriched samples of HL60 cells, while levels of nuclear p62c-fos and p39c-jun were constant.@@@@1@46@@oe@16-12-2010 864135308@GENIA Treebank@formal@@1@S@Nuclei of unstimulated PBL from different donors expressed p62c-fos and p39c-jun, but AP-1 was not detected in the majority of samples.@@@@1@23@@oe@16-12-2010 864135309@GENIA Treebank@formal@@1@S@Following PHA stimulation of PBL, the increase in AP-1 activity was delayed with respect to the augmentation of p39c-jun expression.@@@@1@22@@oe@16-12-2010 864135310@GENIA Treebank@formal@@1@S@We also observed that cytoplasmic p62c-fos and p39c-jun were present in HL60 cells and PHA-stimulated PBL.@@@@1@17@@oe@16-12-2010 864135311@GENIA Treebank@formal@@1@S@However, no cytoplasmic p62c-fos was detected in unstimulated PBL, although in some cases cytoplasmic p39c-jun was detected, suggesting that subcellular compartmentalization of these proteinsmay occur under certain circumstances.@@@@1@33@@oe@16-12-2010 864146701@GENIA Treebank@formal@@1@S@Involvement of intracellular Ca2+ in oxidant-induced NF-kappa B activation.@@@@1@10@@oe@16-12-2010 864146702@GENIA Treebank@formal@@1@S@In human Jurkat T cells and its subclone Wurzburg cells oxidant challenge elevated [Ca2+]i by mobilizing Ca2+ from intracellular stores.@@@@1@21@@oe@16-12-2010 864146703@GENIA Treebank@formal@@1@S@In Jurkat cells this effect was rapid and transient, but in Wurzburg cells the response was slow and sustained.@@@@1@21@@oe@16-12-2010 864146704@GENIA Treebank@formal@@1@S@H2O2-induced NF-kappaB activation in Wurzburg cells was not influenced by the presence of extracellular EGTA but was totally inhibited in cells that were loaded with esterified EGTA.@@@@1@28@@oe@16-12-2010 864146705@GENIA Treebank@formal@@1@S@In Jurkat cells that are not sensitive to H2O2-induced NF-kappaB activation, H2O2 potentiated NF-kappaB activation in the presence of sustained high [Ca2+]i following thapsigargin treatment.@@@@1@27@@oe@16-12-2010 864146706@GENIA Treebank@formal@@1@S@NF-kappaB regulatory effect of alpha-lipoate and N-acetylcysteine appeared to be, at least in part, due to their ability to stabilize elevation of [Ca2+]i following oxidant challenge.@@@@1@29@@oe@16-12-2010 864146707@GENIA Treebank@formal@@1@S@Results of this study indicate that a sustained elevated [Ca2+]i is a significant factor in oxidant-induced NF-kappaB activation.@@@@1@19@@oe@16-12-2010 864180501@GENIA Treebank@formal@@1@S@Effects of interleukin-10 on human peripheral blood mononuclear cell responses to Cryptococcus neoformans, Candida albicans, and lipopolysaccharide.@@@@1@20@@oe@16-12-2010 864180502@GENIA Treebank@formal@@1@S@Deactivation of mononuclear phagocytes is critical to limit the inflammatory response but can be detrimental in the face of progressive infection.@@@@1@22@@oe@16-12-2010 864180503@GENIA Treebank@formal@@1@S@We compared the effects of the deactivating cytokine interleukin 10 (IL-10) on human peripheral blood mononuclear cell (PBMC) responses to lipopolysaccharide (LPS), Cryptococcus neoformans, and Candida albicans.@@@@1@36@@oe@16-12-2010 864180504@GENIA Treebank@formal@@1@S@IL-10 effected dose-dependent inhibition of tumor necrosis factor alpha (TNF-alpha) release in PBMC stimulated by LPS and C. neoformans, with significant inhibition seen with 0.1 U/ml and greater than 90% inhibition noted with 10 U/ml.@@@@1@40@@oe@16-12-2010 864180505@GENIA Treebank@formal@@1@S@In contrast, even at doses as high as 100 U/ml, IL-10 inhibited TNF-alpha release in response to C. albicans by only 50%.@@@@1@26@@oe@16-12-2010 864180506@GENIA Treebank@formal@@1@S@IL-10 profoundly inhibited release of IL-1beta from PBMC stimulated by all three stimuli.@@@@1@14@@oe@16-12-2010 864180507@GENIA Treebank@formal@@1@S@TNF-alpha mRNA and release was inhibited even if IL-10 was added up to 8 h after cryptococcal stimulation.@@@@1@19@@oe@16-12-2010 864180508@GENIA Treebank@formal@@1@S@In contrast, inhibition of IL-1 beta mRNA was of lesser magnitude and occurred only when IL-10 was added within 2 h of cryptococcal stimulation.@@@@1@26@@oe@16-12-2010 864180509@GENIA Treebank@formal@@1@S@IL-10 inhibited translocation of NF-kappaB in response to LPS but not the fungal stimuli.@@@@1@15@@oe@16-12-2010 864180510@GENIA Treebank@formal@@1@S@All three stimuli induced IL-10 production in PBMC, although over 10-fold less IL-10 was released in response to C. neoformans compared with LPS and C. albicans.@@@@1@28@@oe@16-12-2010 864180511@GENIA Treebank@formal@@1@S@Thus, while IL-10 has deactivating effects on PBMC responses to all three stimuli, disparate stimulus- and response-specific patterns of deactivation are seen.@@@@1@25@@oe@16-12-2010 864180512@GENIA Treebank@formal@@1@S@Inhibition by IL-10 of proinflammatory cytokine release appears to occur at the level of gene transcription for TNF-alpha and both transcriptionally and posttranscriptionally for IL-1beta.@@@@1@26@@oe@16-12-2010 864226801@GENIA Treebank@formal@@1@S@HLA-DQB1 codon 57 is critical for peptide binding and recognition.@@@@1@11@@oe@16-12-2010 864226802@GENIA Treebank@formal@@1@S@The association of specific HLA-DQ alleles with autoimmunity is correlated with discrete polymorphisms in the HLA-DQ sequence that are localized within sites suitable for peptide recognition.@@@@1@27@@oe@16-12-2010 864226803@GENIA Treebank@formal@@1@S@The polymorphism at residue 57 of the DQB1 polypeptide is of particular interest since it may play a major structural role in the formation of a salt bridge structure at one end of the peptide-binding cleft of the DQ molecules.@@@@1@41@@oe@16-12-2010 864226804@GENIA Treebank@formal@@1@S@This polymorphism at residue 57 is a recurrent feature of HLA-DQ evolution, occurring in multiple distinct allelic families, which implies a functional selection for maintaining variation at this position in the class II molecule.@@@@1@37@@oe@16-12-2010 864226805@GENIA Treebank@formal@@1@S@We directly tested the amino acid polymorphism at this site as a determinant for peptide binding and for antigen-specific T cell stimulation.@@@@1@23@@oe@16-12-2010 864226806@GENIA Treebank@formal@@1@S@We found that a single Ala-->Asp amino acid 57 substitution in an HLA-DQ3.2 molecule regulated binding of an HSV-2 VP-16-derived peptide.@@@@1@24@@oe@16-12-2010 864226807@GENIA Treebank@formal@@1@S@A complementary single-residue substitution in the peptide abolished its binding to DQ3.2 and converted it to a peptide that can bind to DQ3.1 and DQ3.3 Asp-57-positive MHC molecules.@@@@1@29@@oe@16-12-2010 864226808@GENIA Treebank@formal@@1@S@These binding studies were paralleled by specific T cell recognition of the class II-peptide complex, in which the substituted peptide abolished T cell reactivity, which was directed to the DQ3.2-peptide complex, whereas the same T cell clone recognized the substituted peptide presented by DQ3.3, a class II restriction element differing from DQ3.2 only at residue 57.@@@@1@61@@oe@16-12-2010 864226809@GENIA Treebank@formal@@1@S@This structural and functional complementarity for residue 57 and a specific peptide residue identifies this interaction as a key controlling determinant of restricted recognition in HLA-DQ-specific immune response.@@@@1@29@@oe@16-12-2010 864228201@GENIA Treebank@formal@@1@S@A cell type-specific enhancer in the human B7.1 gene regulated by NF-kappaB.@@@@1@13@@oe@16-12-2010 864228202@GENIA Treebank@formal@@1@S@The costimulatory molecule B7.1 provides a second signal critical for T cell activation.@@@@1@14@@oe@16-12-2010 864228203@GENIA Treebank@formal@@1@S@The distribution of this integral membrane protein is restricted to certain tissues where its level of expression is modulated by multiple exogenous stimuli.@@@@1@24@@oe@16-12-2010 864228204@GENIA Treebank@formal@@1@S@To identify the molecular basis for specificity and inducibility, the chromatin configuration of the human B7.1 gene was examined in intact nuclei from various cell types.@@@@1@28@@oe@16-12-2010 864228205@GENIA Treebank@formal@@1@S@The identification of a tissue-specific deoxyribonuclease I hypersensitive site approximately 3kb upstream of the transcription start site led to the characterization of a cell type-specific enhancer region.@@@@1@28@@oe@16-12-2010 864228206@GENIA Treebank@formal@@1@S@This 183-bp region was both cell type specific and responsive to two distinct stimuli, lipopolysaccharide and dibutyryl cAMP, known to regulate B7.1 expression.@@@@1@26@@oe@16-12-2010 864228207@GENIA Treebank@formal@@1@S@Deletional and site-directed mutagenesis revealed the presence of multiple functionally critical cis elements within this region, one of which was a nuclear factor (NF)-kappaB consensus sequence.@@@@1@31@@oe@16-12-2010 864228208@GENIA Treebank@formal@@1@S@In B7.1-positive B cells, this element bound several members of the NF-kappaB family, transcription factors already implicated in signal transduction pathways relevant to B7.1 expression.@@@@1@28@@oe@16-12-2010 864228209@GENIA Treebank@formal@@1@S@This is the first description, to our knowledge, of regulatory elements that control expression of a gene encoding a B7 costimulatory molecule.@@@@1@25@@oe@16-12-2010 864268601@GENIA Treebank@formal@@1@S@The Epstein-Barr virus-encoded nuclear antigen EBNA-5 accumulates in PML-containing bodies.@@@@1@11@@oe@16-12-2010 864268602@GENIA Treebank@formal@@1@S@EBNA-5 is one of the Epstein-Barr virus (EBV)-encoded nuclear proteins required for immortalization of human B lymphocytes.@@@@1@21@@oe@16-12-2010 864268603@GENIA Treebank@formal@@1@S@In the nuclei of EBV-transformed lymphoblastoid cell lines EBNA-5 is preferentially targetted to distinct nuclear foci.@@@@1@17@@oe@16-12-2010 864268604@GENIA Treebank@formal@@1@S@Previously we have shown (W.Q. Jiang, L.Szekely, V.Wendel-Hansen, N.Ringertz, G.Klein, and A. Rosen, Exp.Cell Res.@@@@1@23@@oe@16-12-2010 864508601@GENIA Treebank@formal@@1@S@Heat shock induces HIV-1 replication in chronically infected promyelocyte cell line OM10.1.@@@@1@13@@oe@16-12-2010 864508602@GENIA Treebank@formal@@1@S@A long period of clinical latency before development of symptoms is characteristic of human immunodeficiency virus type 1 (HIV-1) infection.@@@@1@23@@oe@16-12-2010 864508603@GENIA Treebank@formal@@1@S@OM10.1, a promyelocyte cell line latently infected with HIV-1, has been developed as a model for studying the mechanism of viral latency and the activation of virus expression.@@@@1@31@@oe@16-12-2010 864508604@GENIA Treebank@formal@@1@S@We found that this latently infected cell line with heat shock at 42 degrees C for 2 h resulted in a high level of HIV-1 production without addition of any cytokines.@@@@1@32@@oe@16-12-2010 864508605@GENIA Treebank@formal@@1@S@The mechanism of activation was analyzed by using anti-TNF-alpha antibody and various inhibitors.@@@@1@14@@oe@16-12-2010 864508606@GENIA Treebank@formal@@1@S@Although the TNF-alpha level in culture supernatants was below the sensitivity of an ELISA assay system, addition of anti-TNF-alpha antibody in culture medium could partially suppress the heat shock induced HIV-1 production.@@@@1@34@@oe@16-12-2010 864508607@GENIA Treebank@formal@@1@S@Staurosporine (PKC inhibitor), pentoxifylline (NF-kappa B inhibitor), and Ro5-3335 (HIV-1 Tat inhibitor) also inhibited significantly the heat shock induced virus activation.@@@@1@30@@oe@16-12-2010 864508608@GENIA Treebank@formal@@1@S@In particular, staurosporine achieved approximately 90% inhibition of the HIV-1 antigen expression in heat shock-treated OM10.1 at a non-toxic concentration.@@@@1@23@@oe@16-12-2010 864508609@GENIA Treebank@formal@@1@S@Although the mechanism of HIV-1 activation with heat shock has not been fully elucidated yet, it is presumed PKC plays an important role in HIV-1 activation.@@@@1@28@@oe@16-12-2010 864508610@GENIA Treebank@formal@@1@S@Thus, the present observations will provide a further insight into the pathogenesis of HIV-1 infections.@@@@1@17@@oe@16-12-2010 864525401@GENIA Treebank@formal@@1@S@Abundant expression of erythroid transcription factor P45 NF-E2 mRNA in human peripheral granurocytes.@@@@1@14@@oe@16-12-2010 864525402@GENIA Treebank@formal@@1@S@Transcription factor NF-E2 is crucial for regulation of erythroid-specific gene expression.@@@@1@12@@oe@16-12-2010 864525403@GENIA Treebank@formal@@1@S@p45 subunit of NF-E2 contains a basic-leucine zipper domain and dimerizes with the small Maf family protein to form functional NF-E2 complex.@@@@1@23@@oe@16-12-2010 864525404@GENIA Treebank@formal@@1@S@While p45 expression was shown to be restricted to erythroid cells, megakaryocytes and mast cells in hematopoietic lineage, we found in this study that p45 mRNA is abundantly transcribed in the granulocyte fraction of human peripheral blood cells.@@@@1@41@@oe@16-12-2010 864525405@GENIA Treebank@formal@@1@S@As neutrophils occupy approximately 92% of the cells in granulocyte fraction of human peripheral blood cells.@@@@1@18@@oe@16-12-2010 864525406@GENIA Treebank@formal@@1@S@As neutrophils occupy approximately 92% of the cells in this fraction, the cells expressing p45 is most likely to be neutrophils.@@@@1@24@@oe@16-12-2010 864525407@GENIA Treebank@formal@@1@S@p45 mRNA is also expressed in HL-60 promyelocytes, albeit the expression level is much lower than that of the granulocyte fraction.@@@@1@23@@oe@16-12-2010 864525408@GENIA Treebank@formal@@1@S@HL-60 cells were found to express mafK mRNA, indicating the presence of genuine NF-E2 complex in the cells.@@@@1@20@@oe@16-12-2010 864525409@GENIA Treebank@formal@@1@S@Although p45 mRNA is transcribed from two different promoters, aNF-E2 promoter and fNF-E2 promoter, in erythroid and megakaryocytic lineage cells, p45 mRNA is transcribed only from aNF-E2 promoter.@@@@1@32@@oe@16-12-2010 864525410@GENIA Treebank@formal@@1@S@The expression of p45 megakaryocytic lineage cells, p45 mRNA is transcribed only from aNF-E2 promoter.@@@@1@17@@oe@16-12-2010 864525411@GENIA Treebank@formal@@1@S@The expression of p45 mRNA in the neutrophils declined rapidly after transfer of the cells to in vitro culture and G-CSF could not sustain the expression from the down-regulation, suggesting the E2 may also participate in the regulation of neutrophil-specific gene expression.@@@@1@44@@oe@16-12-2010 864530301@GENIA Treebank@formal@@1@S@Expression of Retinoid X Receptor alpha is increased upon monocytic cell differentiation.@@@@1@13@@oe@16-12-2010 864530302@GENIA Treebank@formal@@1@S@1 alpha, 25-Dihydroxyvitamin D3 (VD) is a potent inducer of monocytic differentiation of both normal and leukemic cells.@@@@1@20@@oe@16-12-2010 864530303@GENIA Treebank@formal@@1@S@Its effects are mediated by its nuclear receptor (VDR).@@@@1@12@@oe@16-12-2010 864530304@GENIA Treebank@formal@@1@S@Efficient gene activation requires the heterodimerization of VDR with Retinoid X Receptors (RXR).@@@@1@16@@oe@16-12-2010 864530305@GENIA Treebank@formal@@1@S@In the present study using specific antibodies, we analyzed the expression of the RXR alpha protein in blood mononuclear cells from acute myeloid patients (AML) (10 cases) and from myelomonocytic cell lines arrested at different stages of differentiation.@@@@1@44@@oe@16-12-2010 864530306@GENIA Treebank@formal@@1@S@We observed that the RXR alpha expression increased during myelomonocytic differentiation, since the highest levels were found in AML samples and in myelomonocytic cell lines having the highest amounts of monocytic precursors.@@@@1@34@@oe@16-12-2010 864530307@GENIA Treebank@formal@@1@S@We also demonstrated that fresh leukemic cells, whatever their stage of differentiation, as well as myelomonocytic cell lines, respond to VD by an increase in RXR alpha levels.@@@@1@32@@oe@16-12-2010 864530308@GENIA Treebank@formal@@1@S@Combinations of all-trans retinoic acid (RA) and VD, in some cases, increased this effect.@@@@1@19@@oe@16-12-2010 864530309@GENIA Treebank@formal@@1@S@This response suggests the involvement of RXR alpha in monocytic differentiation upon VD treatment.@@@@1@15@@oe@16-12-2010 864561601@GENIA Treebank@formal@@1@S@Putative steroid binding domain of the human mineralocorticoid receptor, expressed in E. coli in the presence of heat shock proteins shows typical native receptor characteristics.@@@@1@27@@oe@16-12-2010 864561602@GENIA Treebank@formal@@1@S@Domain E, considered as the putative hormone binding domain (HBD) of the human mineralocorticoid receptor (hMR) was expressed in Escherichia coli as a fusion protein with either maltose binding protein (MBP) or glutathione S-transferase (GST).@@@@1@45@@oe@16-12-2010 864561603@GENIA Treebank@formal@@1@S@These bacterially-produced MR constructs had no steroid binding activity per se.@@@@1@12@@oe@16-12-2010 864561604@GENIA Treebank@formal@@1@S@In fact, heat shock protein association (hsp) is required for high affinity ligand-binding of the MR.@@@@1@20@@oe@16-12-2010 864561605@GENIA Treebank@formal@@1@S@After incubation of purified MBP- or GST-HBD with rabbit reticulocyte lysate, known to be rich in heat shock proteins, we obtained saturable binding of [3H]aldosterone.@@@@1@28@@oe@16-12-2010 864561606@GENIA Treebank@formal@@1@S@The Kd value for aldosterone was 0.3 nM and the Bmax = 32 pmol/mg.@@@@1@15@@oe@16-12-2010 864561607@GENIA Treebank@formal@@1@S@Hormone binding specificity was assessed by competition studies with various steroid ligands.@@@@1@13@@oe@16-12-2010 864561608@GENIA Treebank@formal@@1@S@Sucrose gradient assays performed with [3H]aldosterone-MBP-HBD revealed complex sedimenting at 8.3S and 4.9S with [3H]progesterone-MBP-HBD.@@@@1@16@@oe@16-12-2010 864561609@GENIA Treebank@formal@@1@S@Western-blot analysis of the sedimentation peak showed the concomitant presence of MBP-HBD by a monoclonal anti-MBP antibody, and hsp90 by a monoclonal anti-hsp antibody.@@@@1@26@@oe@16-12-2010 864561610@GENIA Treebank@formal@@1@S@Moreover, following incubation with the anti-rabbit hsp90 monoclonal antibody the sedimenting gradient showed a 10.4S sedimenting complex.@@@@1@19@@oe@16-12-2010 864561611@GENIA Treebank@formal@@1@S@These analyses demonstrated that the [3H]aldosterone-MBP-HBD complex is at least associated with hsp90 in reticulocyte lysate and that the HBD of hMR is sufficient to bind hsp90.@@@@1@28@@oe@16-12-2010 864561612@GENIA Treebank@formal@@1@S@Deletions of a relatively short amino- (729-766) or carboxy- terminal (940-984) region of the HBD fragment eliminated all steroid-binding properties.@@@@1@24@@oe@16-12-2010 864561613@GENIA Treebank@formal@@1@S@Overall, these results indicate that the integrity of domain E is necessary and sufficient to bind steroid ligands, agonists or antagonists, with characteristics similar to the entire native MR.@@@@1@33@@oe@16-12-2010 864977901@GENIA Treebank@formal@@1@S@Inhibition of p105 processing by NF-kappaB proteins in transiently transfected cells.@@@@1@12@@oe@16-12-2010 864977902@GENIA Treebank@formal@@1@S@Regulation of the transcription factor NF-kappaB involves proteasome-mediated processing of the NF-kappaB1 p105 precursor protein, which generates the p50 subunit of NF-kappaB.@@@@1@24@@oe@16-12-2010 864977903@GENIA Treebank@formal@@1@S@The processing of p105 occurs constitutively in vivo but can be markedly enhanced by various cellular activation agents, although the underlying regulatory mechanism is not yet clear.@@@@1@29@@oe@16-12-2010 864977904@GENIA Treebank@formal@@1@S@In the present study, we demonstrate that signal-mediated induction of p105 processing in human T cells is associated with de novo synthesis of this precursor protein.@@@@1@28@@oe@16-12-2010 864977905@GENIA Treebank@formal@@1@S@Transient transfection studies performed in COS7 cells revealed that the newly synthesized p105 protein appears to be more rapidly processed compared to its accumulated form that is already associated with the processed product p50.@@@@1@35@@oe@16-12-2010 864977906@GENIA Treebank@formal@@1@S@Interestingly, the processing rate of p105 is markedly inhibited in cells co-transfected with p50 or other NF-kappaB subunits, including RelA and c-Rel, that physically interact with p105.@@@@1@31@@oe@16-12-2010 864977907@GENIA Treebank@formal@@1@S@These findings suggest that the processing of p105 is subject to negative regulation by the various NF-kappaB subunits.@@@@1@19@@oe@16-12-2010 864977908@GENIA Treebank@formal@@1@S@We further demonstrate that p105 undergoes degradation in lipopolysaccharide-stimulated human monocytic cells.@@@@1@13@@oe@16-12-2010 864977909@GENIA Treebank@formal@@1@S@However, the inducible degradation of p105 is not coupled with the generation of p50.@@@@1@16@@oe@16-12-2010 864977910@GENIA Treebank@formal@@1@S@Together, these studies demonstrate that the processing and inducible degradation of p105 are differentially regulated.@@@@1@17@@oe@16-12-2010 864982201@GENIA Treebank@formal@@1@S@Identification of a human LIM-Hox gene, hLH-2, aberrantly expressed in chronic myelogenous leukaemia and located on 9q33-34.1.@@@@1@20@@oe@16-12-2010 864982202@GENIA Treebank@formal@@1@S@We describe the isolation of human LH-2, a putative transcription factor containing two cysteine-rich regions (LIM domains) and a homeobox (Hox) DNA-binding domain.@@@@1@29@@oe@16-12-2010 864982203@GENIA Treebank@formal@@1@S@High levels of hLH-2 expression were observed in all cases of chronic myelogenous leukaemia (CML) tested, regardless of disease status.@@@@1@24@@oe@16-12-2010 864982204@GENIA Treebank@formal@@1@S@hLH-2 was mapped to chromosome 9Q33-34.1, in the same region as the reciprocal translocation that creates the BCR-ABL chimera of the Philadelphia chromosome (Ph'), the hallmark of CML; hLH-2 was retained on the derivative 9 chromosome and is therefore centromeric of c-ABL.@@@@1@49@@oe@16-12-2010 864982205@GENIA Treebank@formal@@1@S@The proximity of hLH-2 to the breakpoint on chromosome 9 raises the possibility of cis-activation by the t(9;22)(q34;q11) translocation.@@@@1@20@@oe@16-12-2010 864982206@GENIA Treebank@formal@@1@S@In addition to finding hLH-2 expression in all cases of CML, expression was observed in lymphoid malignancies and myeloid cell lines, but not in primary cases of acute myelogenous leukaemia.@@@@1@33@@oe@16-12-2010 864982207@GENIA Treebank@formal@@1@S@The role of hLH-2 in the development or progression of leukaemia is not known.@@@@1@15@@oe@16-12-2010 864982208@GENIA Treebank@formal@@1@S@However, hLH-2 may prove useful as a marker of CML for monitoring residual disease.@@@@1@16@@oe@16-12-2010 865284101@GENIA Treebank@formal@@1@S@BCL-6 expression during B-cell activation.@@@@1@6@@oe@16-12-2010 865284102@GENIA Treebank@formal@@1@S@Translocations involving the BCL-6 gene are common in the diffuse large cell subtype of non-Hodgkin's lymphoma.@@@@1@18@@oe@16-12-2010 865284103@GENIA Treebank@formal@@1@S@Invariably, the BCL-6 coding region is intact, but its 5' untranslated region is replaced with sequences from the translocation partner.@@@@1@23@@oe@16-12-2010 865284104@GENIA Treebank@formal@@1@S@The present study shows that BCL-6 expression is regulated in lymphocytes during mitogenic stimulation.@@@@1@15@@oe@16-12-2010 865284105@GENIA Treebank@formal@@1@S@Resting B and T lymphocytes contain high levels of BCL-6 mRNA.@@@@1@12@@oe@16-12-2010 865284106@GENIA Treebank@formal@@1@S@Stimulation of mouse B cells with anti-IgM or IgD antibodies, bacterial lipopolysaccharide, phorbol 12-myristate 13-acetate plus ionomycin, or CD40 ligand led to a five-fold to 35-fold decrease in BCL-6 mRNA levels.@@@@1@35@@oe@16-12-2010 865284107@GENIA Treebank@formal@@1@S@Similar downregulation of BCL-6 mRNA was seen in human B cells stimulated with Staphylococcus aureus plus interleukin-2 or anti-IgM antibodies and in human T lymphocytes stimulated with phytohemagglutinin.@@@@1@29@@oe@16-12-2010 865284108@GENIA Treebank@formal@@1@S@BCL-6 mRNA levels began to decrease 8 to 16 hours after stimulation, before cells entered S phase.@@@@1@19@@oe@16-12-2010 865284109@GENIA Treebank@formal@@1@S@Although polyclonal activation of B cells in vitro invariably decreased BCL-6 MRNA expression, activated B cells from human germinal centers expressed BCL-6 mRNA at levels comparable to the levels in resting B cells.@@@@1@35@@oe@16-12-2010 865284110@GENIA Treebank@formal@@1@S@Despite these similar mRNA levels, BCL-6 protein expression was threefold to 34-fold higher in germinal center B cells than in resting B cells, suggesting that BCL-6 protein levels are controlled by translational or posttranslational mechanisms.@@@@1@38@@oe@16-12-2010 865284111@GENIA Treebank@formal@@1@S@These observations suggest that the germinal center reaction provides unique activation signals to B cells that allow for continued, high-level BCL-6 expression.@@@@1@24@@oe@16-12-2010 865495101@GENIA Treebank@formal@@1@S@An element upstream from the human delta-globin-encoding gene specifically enhances beta-globin reporter gene expression in murine erythroleukemia cells.@@@@1@19@@oe@16-12-2010 865495102@GENIA Treebank@formal@@1@S@We have previously shown that a DNA-binding factor specific to adult hematopoietic cells (polypryrimidine-binding factor, PYBF) binds to a pyrimidine-rich region 1 kb upstream from the human delta-globin-encoding gene (HBD).@@@@1@36@@oe@16-12-2010 865495103@GENIA Treebank@formal@@1@S@The developmental stage-specificity of PYBF and the location of its binding site between the fetal and adult beta-globin (HBB)-like genes suggest that PBYF and its binding site may function in fetal-to-adult globin gene switching.@@@@1@38@@oe@16-12-2010 865495104@GENIA Treebank@formal@@1@S@Here, we describe the effect of 383-bp (delta383) and 99-bp (delta99) sequences containing the PYBF-binding site on transcription from various globin and non-globin promoters, using a transient assay with the cat reporter gene in murine erythroleukemia (MEL) cells, a cell line with abundant PYBF activity.@@@@1@55@@oe@16-12-2010 865495105@GENIA Treebank@formal@@1@S@We show that both delta383 and delta99 specifically enhance expression of cat for plasmids containing a human adult globin (HBB) promoter, whereas expression of similar constructs using human fetal (A gamma-) globin (HBG1) or simian virus 40 (SV40) promoters is not enhanced.@@@@1@52@@oe@16-12-2010 865495106@GENIA Treebank@formal@@1@S@The results suggest that PYBF and the pyrimidine-rich region upstream from HBD can specifically enhance HBB transcription in adult erythroid cells.@@@@1@22@@oe@16-12-2010 865710101@GENIA Treebank@formal@@1@S@A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes.@@@@1@20@@oe@16-12-2010 865710102@GENIA Treebank@formal@@1@S@We have isolated a novel cDNA clone encoding interferon (IFN) consensus sequence-binding protein in adult T-cell leukemia cell line or activated T cells (ICSAT); this protein is the human homolog of the recently cloned Pip/LSIRF.@@@@1@41@@oe@16-12-2010 865710103@GENIA Treebank@formal@@1@S@ICSAT is structurally most closely related to the previously cloned ICSBP, a member of the IFN regulatory factor (IRF) family of proteins that binds to interferon consensus sequences (ICSs) found in many promoters of the IFN-regulated genes.@@@@1@43@@oe@16-12-2010 865710104@GENIA Treebank@formal@@1@S@Among T-cell lines investigated, ICSAT was abundantly expressed in human T-cell leukemia virus type 1 (HTLV-1)-infected T cells.@@@@1@23@@oe@16-12-2010 865710105@GENIA Treebank@formal@@1@S@When the HTLV-1 tax gene was expressed or phorbol myristake acetate-A23187 stimulation was used, ICSAT expression was induced in Jurkat cells which otherwise do not express ICSAT.@@@@1@29@@oe@16-12-2010 865710106@GENIA Treebank@formal@@1@S@When the binding of ICSAT to four different ICSs was tested, the relative differences in binding affinities for those ICSs were determined.@@@@1@24@@oe@16-12-2010 865710107@GENIA Treebank@formal@@1@S@To study the functional role of ICSAT, we performed cotransfection experiments with the human embryonal carcinoma cell line N-Tera2.@@@@1@21@@oe@16-12-2010 865710108@GENIA Treebank@formal@@1@S@ICSAT was demonstrated to possess repressive function over the gene activation induced by IFN stimulation or by IRF-1 cotransfection.@@@@1@20@@oe@16-12-2010 865710109@GENIA Treebank@formal@@1@S@Such repressive function is similar to that seen in IRF-2 or ICSBP.@@@@1@13@@oe@16-12-2010 865710110@GENIA Treebank@formal@@1@S@However, we have found that ICSAT has a different repressive effect from that of IRF-2 or ICSBP in some IFN-responsive reporter constructs.@@@@1@24@@oe@16-12-2010 865710111@GENIA Treebank@formal@@1@S@These results suggest that a novel mechanism of gene regulation by "differential repression" is used by multiple members of repressor proteins with different repressive effects on the IFN-responsive genes.@@@@1@32@@oe@16-12-2010 865711501@GENIA Treebank@formal@@1@S@Inhibition of alpha interferon but not gamma interferon signal transduction by phorbol esters is mediated by a tyrosine phosphatase.@@@@1@20@@oe@16-12-2010 865711502@GENIA Treebank@formal@@1@S@Previous studies have indicated that the expression of viral oncoproteins, cell transformation, or phorbol ester treatment of cells can inhibit alpha/beta interferon (IFN-alpha/beta)-induced gene expression.@@@@1@31@@oe@16-12-2010 865711503@GENIA Treebank@formal@@1@S@The mechanisms by which these promoters of cell growth exert their inhibitory effects vary, but in most instances they involve a disruption of the IFN-alpha/beta-induced transcription complex ISGF3 such that the DNA-binding component of this complex (the 48-kDa ISGF3gamma protein) does not bind to the interferon-stimulated response element (ISRE).@@@@1@55@@oe@16-12-2010 865711504@GENIA Treebank@formal@@1@S@In this report, we demonstrated that phorbol ester treatment of human peripheral blood monocytes dramatically inhibits activation of IFN-alpha/B-stimulated early response genes but by a mechanism which does not involve abrogation of the ISRE binding of ISGF3gamma.@@@@1@39@@oe@16-12-2010 865711505@GENIA Treebank@formal@@1@S@Phorbol ester treatment of monocytes inhibited IFN alpha-stimulated tyrosine phosphorylation of the transcription factors Stat1alpha, Stat2, and Stat3 and of the tyrosine kinase Tyk2 but had no effect on IFN-gamma activation of Stat1alpha.@@@@1@36@@oe@16-12-2010 865711506@GENIA Treebank@formal@@1@S@IFNalpha-stimulated tyrosine phosphorylation of Jak1 and the alpha subunit of the IFN-alpha receptor were unaffected by phorbol 12-myristate 13-acetate (PMA).@@@@1@23@@oe@16-12-2010 865711507@GENIA Treebank@formal@@1@S@Moreover, PMA caused the dephosphorylation of Tyk2 but not of Jak1, which was activated by IFN.@@@@1@19@@oe@16-12-2010 865711508@GENIA Treebank@formal@@1@S@Pretreatment of cells with vanadate prevented the effects of PMA with regard to PMA-induced Tyk2 dephosphorylation.@@@@1@17@@oe@16-12-2010 865711509@GENIA Treebank@formal@@1@S@These observations suggest that PMA exerts its inhibitory effects by activation of a tyrosine phosphatase which selectively regulates Tyk2 but not Jak1 activity.@@@@1@24@@oe@16-12-2010 865714301@GENIA Treebank@formal@@1@S@The myeloid-cell-specific c-fes promoter is regulated by Sp1, PU.1, and a novel transcription factor.@@@@1@17@@oe@16-12-2010 865714302@GENIA Treebank@formal@@1@S@The protein product of the c-fps/fes (c-fes) proto-oncogene has been implicated in the normal development of myeloid cells (macrophages and neutrophils).@@@@1@26@@oe@16-12-2010 865714303@GENIA Treebank@formal@@1@S@mRNA for c-fes has been detected exclusively in myeloid cells and vascular endothelial cells in adult mammals.@@@@1@18@@oe@16-12-2010 865714304@GENIA Treebank@formal@@1@S@Although a 13-kilobase-pair (kb) human c-fes transgene exhibits high levels of expression in mice, the sequences that confer myeloid-cell-specific expression of the human c-fes gene have not been defined.@@@@1@33@@oe@16-12-2010 865714305@GENIA Treebank@formal@@1@S@Transient-transfection experiments demonstrated that plasmids containing 446 bp of c-fes 5'-flanking sequences linked to a luciferase reporter gene were active exclusively in myeloid cells.@@@@1@25@@oe@16-12-2010 865714306@GENIA Treebank@formal@@1@S@No other DNA element within the 13-kb human c-fes locus contained positive cis-acting elements, with the exception of a weakly active region within the 3'-flanking sequences.@@@@1@28@@oe@16-12-2010 865714307@GENIA Treebank@formal@@1@S@DNase I footprinting assays revealed four distinct sites that bind myeloid nuclear proteins (-408 to -386, -293 to -254, -76 to -65, and -34 to +3).@@@@1@32@@oe@16-12-2010 865714308@GENIA Treebank@formal@@1@S@However, the first two footprints resided in sequences that were largely dispensable for transient activity.@@@@1@17@@oe@16-12-2010 865714309@GENIA Treebank@formal@@1@S@Plasmids containing 151 bp of 5'-flanking sequences confer myeloid-cell-specific gene expression.@@@@1@12@@oe@16-12-2010 865714310@GENIA Treebank@formal@@1@S@Electrophoretic mobility shift analyses demonstrated that the 151-bp region contains nuclear protein binding sites for Sp1, PU.1, and/or Elf-1, and a novel factor.@@@@1@27@@oe@16-12-2010 865714311@GENIA Treebank@formal@@1@S@This unidentified factor binds immediately 3' of the PU.1/Elf-1 sites and appears to be myeloid cell specific.@@@@1@18@@oe@16-12-2010 865714312@GENIA Treebank@formal@@1@S@Mutation of the PU.1/Elf-1 site or the 3' site (FP4-3') within the context of the c-fes promoter resulted in substantially reduced activity in transient transfections.@@@@1@28@@oe@16-12-2010 865714313@GENIA Treebank@formal@@1@S@Furthermore, transient-cotransfection assay demonstrated that PU.1 (and not Elf-1) can transactivate the c-fes promoter in nonmyeloid cell lines.@@@@1@22@@oe@16-12-2010 865714314@GENIA Treebank@formal@@1@S@We conclude that the human c-fes gene contains a strong myeloid-cell-specific promoter that is regulated by Sp1, PU.1, and a novel transcription factor.@@@@1@26@@oe@16-12-2010 865715301@GENIA Treebank@formal@@1@S@Transcriptional activation of RNA polymerase III-dependent genes by the human T-cell leukemia virus type 1 tax protein.@@@@1@18@@oe@16-12-2010 865715302@GENIA Treebank@formal@@1@S@The human T-cell leukemia virus-encoded tax protein is a potent activator of many viral and cellular genes transcribed by RNA polymerase II.@@@@1@23@@oe@16-12-2010 865715303@GENIA Treebank@formal@@1@S@We find that both chromatin and cell extracts derived from human T-cell leukemia virus type 1-infected human T lymphocytes support higher levels of 5S rRNA and tRNA gene transcription than chromatin or extracts from uninfected T lymphocytes.@@@@1@38@@oe@16-12-2010 865715304@GENIA Treebank@formal@@1@S@The viral protein Tax was likely responsible for this higher level of class II gene transcription, as purified Tax was found to stimulate both genes when added to the uninfected cell extract or in reconstituted systems.@@@@1@38@@oe@16-12-2010 865715305@GENIA Treebank@formal@@1@S@Both limiting-component transcription assays and DNA binding assays identified the class III gene transcription factor TFIIIB as the principle target of Tax activity.@@@@1@24@@oe@16-12-2010 865715306@GENIA Treebank@formal@@1@S@Surprisingly, we find that Tax increases the effective concentration of active TFIIIB molecules.@@@@1@15@@oe@16-12-2010 865715307@GENIA Treebank@formal@@1@S@These data suggest that Tax stimulates RNA polymerase III-dependent gene expression by accelerating the rate and/or extent of transcription initiation complex assembly.@@@@1@23@@oe@16-12-2010 865919001@GENIA Treebank@formal@@1@S@Transcription factors of T and B lymphocytes--basic research and clinical perspectives for gastroenterology.@@@@1@16@@oe@16-12-2010 865919002@GENIA Treebank@formal@@1@S@Tissue specific regulation of gene expression by transcription factors is a fascinating new field in molecular immunology.@@@@1@18@@oe@16-12-2010 865919003@GENIA Treebank@formal@@1@S@This review summarizes data on specific regulation of promoters and enhancers by nuclear trans-acting factors in lymphocytes.@@@@1@18@@oe@16-12-2010 865919004@GENIA Treebank@formal@@1@S@The structural classes of transcription factors are described and basic methods for detection and analysis of transcription factors are detailed.@@@@1@21@@oe@16-12-2010 865919005@GENIA Treebank@formal@@1@S@Furthermore, the most important trans-acting factors of T and B lymphocytes (e.g. NF-kB, NF-AT and STAT families) and their functional importance are described.@@@@1@28@@oe@16-12-2010 865919006@GENIA Treebank@formal@@1@S@Several methods for specific down-regulation of transcription factors are shown that may be relevant to treatment of human disease.@@@@1@20@@oe@16-12-2010 865919007@GENIA Treebank@formal@@1@S@The data are discussed with regard to their potential clinical relevance for gastroenterology.@@@@1@14@@oe@16-12-2010 866266601@GENIA Treebank@formal@@1@S@DNA triplex formation selectively inhibits granulocyte-macrophage colony-stimulating factor gene expression in human T cells.@@@@1@15@@oe@16-12-2010 866266602@GENIA Treebank@formal@@1@S@Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hemopoietic growth factor that is expressed in activated T cells, fibroblasts, macrophages, and endothelial cells.@@@@1@27@@oe@16-12-2010 866266603@GENIA Treebank@formal@@1@S@Although GM-CSF does not appear to be essential for normal hemopoiesis, overexpression of GM-CSF has been implicated in the pathogenesis of some diseases such as myeloid leukemia and chronic inflammation.@@@@1@32@@oe@16-12-2010 866266604@GENIA Treebank@formal@@1@S@An NF-kappaB/Rel binding site within the GM-CSF promoter, termed the kappaB element appears to be important for controlling expression in reporter gene assays in response to a number of stimuli in T cells.@@@@1@35@@oe@16-12-2010 866266605@GENIA Treebank@formal@@1@S@We investigated oligonucleotide-directed triple helix formation across this regulatory sequence as a potential tool to inhibit GM-CSF gene transcription.@@@@1@20@@oe@16-12-2010 866266606@GENIA Treebank@formal@@1@S@A 15-base oligonucleotide, GM3, was targeted to a purine-rich region in the GM-CSF proximal promoter, which overlaps the kappaB element.@@@@1@24@@oe@16-12-2010 866266607@GENIA Treebank@formal@@1@S@Gel mobility shift assays and DNase I footprinting demonstrated that GM3 formed a sequence-specific collinear triplex with its double-stranded DNA target.@@@@1@22@@oe@16-12-2010 866266608@GENIA Treebank@formal@@1@S@Triplex formation by GM3 blocked recombinant and nuclear NF-kappaB proteins binding to the GM-CSF element.@@@@1@16@@oe@16-12-2010 866266609@GENIA Treebank@formal@@1@S@GM3 also caused selective inhibition of the human T-cell lymphotrophic virus-1 Tax transactivator-induced luciferase activity from a reporter construct driven by the GM-CSF promoter in Jurkat T cells.@@@@1@29@@oe@16-12-2010 866266610@GENIA Treebank@formal@@1@S@Finally, GM3 greatly reduced the concentration of endogenous GM-CSF mRNA induced by different stimuli in Jurkat T cells but did not affect interleukin 3 mRNA levels in the same cells.@@@@1@32@@oe@16-12-2010 866266611@GENIA Treebank@formal@@1@S@We conclude that the kappaB element in the GM-CSF promoter plays a central role in the transcriptional activation of the endogenous GM-CSF gene.@@@@1@24@@oe@16-12-2010 866266612@GENIA Treebank@formal@@1@S@Colinear triplex formation acts as a selective transcriptional repressor of the GM-CSF gene and may have potential therapeutic application in cases of undesirable overexpression of this protein.@@@@1@28@@oe@16-12-2010 866284501@GENIA Treebank@formal@@1@S@Cooperation between core binding factor and adjacent promoter elements contributes to the tissue-specific expression of interleukin-3.@@@@1@17@@oe@16-12-2010 866284502@GENIA Treebank@formal@@1@S@Tissue-specific expression of interleukin-3 (IL-3) is mediated via cis-acting elements located within 315 base pairs of the transcription start.@@@@1@22@@oe@16-12-2010 866284503@GENIA Treebank@formal@@1@S@This is achieved in part through the positive activities of the AP-1 and Elf-1 sites in the IL-3 promoter.@@@@1@20@@oe@16-12-2010 866284504@GENIA Treebank@formal@@1@S@The contribution to T cell-specific expression by other promoter sites was assessed in a transient expression assay with IL-3 promoter constructs linked to a luciferase gene, focusing initially on the core binding factor (CBF) site, which is footprinted in vivo upon T cell activation.@@@@1@49@@oe@16-12-2010 866284505@GENIA Treebank@formal@@1@S@Activity of the CBF site is shown to be critically dependent on the adjacent activator site Act-1.@@@@1@18@@oe@16-12-2010 866284506@GENIA Treebank@formal@@1@S@Together the Act-1 and CBF sites form a functional unit (AC unit) with dual activity.@@@@1@18@@oe@16-12-2010 866284507@GENIA Treebank@formal@@1@S@The AC unit is demonstrated to enhance basal activity of promoters both in fibroblasts and T cells.@@@@1@18@@oe@16-12-2010 866284508@GENIA Treebank@formal@@1@S@This activity is further inducible in activated T cells, but not in fibroblasts.@@@@1@15@@oe@16-12-2010 866284509@GENIA Treebank@formal@@1@S@In addition to the already identified NIP repressor site, evidence is presented for a second repressor region that restricts promoter activity in fibroblasts.@@@@1@25@@oe@16-12-2010 866284510@GENIA Treebank@formal@@1@S@Finally, a novel positive regulatory element has been mapped in the IL-3 promoter between nucleotide -180 and -210 that leads to increased expression in T cells.@@@@1@28@@oe@16-12-2010 866284511@GENIA Treebank@formal@@1@S@Together these results demonstrate that T cell expression of IL-3 is not specified by the activity of a single tissue-specific element, but instead involves multiple interacting elements that provide both specific positive regulation in T cells and specific negative regulation in fibroblasts.@@@@1@44@@oe@16-12-2010 866292801@GENIA Treebank@formal@@1@S@Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements.@@@@1@22@@oe@16-12-2010 866292802@GENIA Treebank@formal@@1@S@The cytoplasmic domain of the receptor for interleukin 10 (IL-10R) contains two box 3 sequence motifs that have been identified in the signal-transducing receptor subunits for IL-6-type cytokines and noted to be required for activating STAT3 and inducing transcription through IL-6-responsive elements.@@@@1@45@@oe@16-12-2010 866292803@GENIA Treebank@formal@@1@S@To determine whether the IL-10R has signaling functions similar to IL-6R in cells normally expressing these receptors, leukocytes of the B-, T-, and NK-cell lineages were treated with either cytokine.@@@@1@34@@oe@16-12-2010 866292804@GENIA Treebank@formal@@1@S@Both cytokines activated factors that bound to the sis-inducible element and included STAT1 and STAT3.@@@@1@16@@oe@16-12-2010 866292805@GENIA Treebank@formal@@1@S@The cell response to IL-10 characteristically differed from that to IL-2/IL-15, IL-4, and interferon gamma.@@@@1@18@@oe@16-12-2010 866292806@GENIA Treebank@formal@@1@S@The signaling capabilities of the IL-10R for activating specific STAT proteins and inducing gene transcription were defined by reconstitution of receptor functions in transfected tissue culture cells.@@@@1@28@@oe@16-12-2010 866292807@GENIA Treebank@formal@@1@S@COS-1 cells, co-expressing the human IL-10R and individual STAT proteins, confirmed a preference of the IL-10R for STAT3 and STAT1.@@@@1@23@@oe@16-12-2010 866292808@GENIA Treebank@formal@@1@S@Unlike many hematopoietin receptors, the IL-10R did not detectably activate STAT5.@@@@1@13@@oe@16-12-2010 866292809@GENIA Treebank@formal@@1@S@The IL-10R, together with reporter gene constructs containing different IL-6-responsive gene elements, reconstituted in hepatoma cells an induction of transcription by IL-10 that was comparable to that by IL-6.@@@@1@32@@oe@16-12-2010 866292810@GENIA Treebank@formal@@1@S@This regulation could not be appreciably modified by enhanced expression of STAT proteins.@@@@1@14@@oe@16-12-2010 866292811@GENIA Treebank@formal@@1@S@The similar actions of IL-10R and IL-6R on the induction of endogenous IL-6-responsive genes were demonstrated in hepatoma cells stably expressing the IL-10R.@@@@1@24@@oe@16-12-2010 866292812@GENIA Treebank@formal@@1@S@These receptor functions required the presence of the box 3 motifs, as shown by the analysis of the mouse IL-10R constructs containing progressively truncated cytoplasmic domains.@@@@1@28@@oe@16-12-2010 866292813@GENIA Treebank@formal@@1@S@The data demonstrate that the IL-10R, unlike other members of the interferon receptor family, is highly effective in recruiting the signaling pathways of IL-6-type cytokine receptors.@@@@1@29@@oe@16-12-2010 866296001@GENIA Treebank@formal@@1@S@Globin gene switching.@@@@1@4@@oe@16-12-2010 866296002@GENIA Treebank@formal@@1@S@In vivo protein-DNA interactions of the human beta-globin locus in erythroid cells expressing the fetal or the adult globin gene program.@@@@1@22@@oe@16-12-2010 866296003@GENIA Treebank@formal@@1@S@To characterize the protein-DNA interactions important for the developmental control of the human beta-globin locus, we analyzed by in vivo dimethyl sulfate footprinting erythroid cells expressing either the fetal or the adult globin developmental program.@@@@1@37@@oe@16-12-2010 866296004@GENIA Treebank@formal@@1@S@In the locus control region (LCR) of the beta-globin locus, in vivo footprints on NF-E2 (or AP-1) and GATA-1 motifs remained the same regardless of whether the fetal or the adult globin genes are expressed.@@@@1@41@@oe@16-12-2010 866296005@GENIA Treebank@formal@@1@S@In contrast, in vivo footprints on GT (CACCC) motifs differed between the cells expressing the fetal or the adult globin program.@@@@1@25@@oe@16-12-2010 866296006@GENIA Treebank@formal@@1@S@In promoter regions, the actively transcribed genes demonstrated extensive and consistent footprints over the canonical elements, such as CACCC and CCAAT motifs.@@@@1@25@@oe@16-12-2010 866296007@GENIA Treebank@formal@@1@S@The adult globin expressing cells displayed more extensive footprints than the fetal globin expressing cells in the 3' regulatory sequences of both the Agamma- and the beta-globin genes, suggesting a role of these 3' elements in beta-globin gene expression.@@@@1@41@@oe@16-12-2010 866296008@GENIA Treebank@formal@@1@S@Our results suggest that the bulk of protein-DNA interactions that underlies the developmental control of globin genes takes place in the gamma- and beta-globin gene promoters, and that GT motifs of the beta-globin locus LCR may play a role in the developmental regulation of human beta-globin gene expression, perhaps by increasing the probability of interaction of the LCR holocomplex with the fetal or the adult globin gene.@@@@1@70@@oe@16-12-2010 866302201@GENIA Treebank@formal@@1@S@Octamer binding factors and their coactivator can activate the murine PU.1 (spi-1) promoter.@@@@1@16@@oe@16-12-2010 866302202@GENIA Treebank@formal@@1@S@PU.1 (spi-1), a member of the Ets transcription factor family, is predominantly expressed in myeloid and B cells, activates many B cell and myeloid genes, and is critical for development of both of these lineages.@@@@1@42@@oe@16-12-2010 866302203@GENIA Treebank@formal@@1@S@Our previous studies (Chen, H.M., Ray-Gallet, D., Zhang, P., Hetherington, C.J., Gonzalez, D.A., Zhang, D.-E., Moreau-Gachelin, F., and Tenen, D.G.(1995) Oncogene 11, 1549-1560) demonstrate that the PU.1 promoter directs cell type-specific reporter gene expression in myeloid cell lines, and that PU.1 activates its own promoter in an autoregulatory loop.@@@@1@72@@oe@16-12-2010 866302204@GENIA Treebank@formal@@1@S@Here we show that the murine PU.1 promoter is also specifically and highly functional in B cell lines as well.@@@@1@21@@oe@16-12-2010 866302205@GENIA Treebank@formal@@1@S@Oct-1 and Oct-2 can bind specifically to a site at base pair -55 in vitro, and this site is specifically protected in B cells in vivo.@@@@1@28@@oe@16-12-2010 866302206@GENIA Treebank@formal@@1@S@We also demonstrate that two other sites contribute to promoter activity in B cells; an Sp1 binding site adjacent to the octamer site, and the PU.1 autoregulatory site.@@@@1@31@@oe@16-12-2010 866302207@GENIA Treebank@formal@@1@S@Finally, we show that the B cell coactivator OBF-1/Bob1/OCA-B is only expressed in B cells and not in myeloid cells, and that OBF-1/Bob1/OCA-B can transactivate the PU.1 promoter in HeLa and myeloid cells.@@@@1@36@@oe@16-12-2010 866302208@GENIA Treebank@formal@@1@S@This B cell restricted coactivator may be responsible for the B cell specific expression of PU.1 mediated by the octamer site.@@@@1@22@@oe@16-12-2010 866306001@GENIA Treebank@formal@@1@S@Tissue-specific activity of the gammac chain gene promoter depends upon an Ets binding site and is regulated by GA-binding protein.@@@@1@21@@oe@16-12-2010 866306002@GENIA Treebank@formal@@1@S@The gammac chain is a subunit of multiple cytokine receptors (interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15), the expression of which is restricted to hematopoietic lineages.@@@@1@37@@oe@16-12-2010 866306003@GENIA Treebank@formal@@1@S@A defect in gammac leads to the X-linked severe combined immunodeficiency characterized by a block in T cell differentiation.@@@@1@20@@oe@16-12-2010 866306004@GENIA Treebank@formal@@1@S@In order to better characterize the human gammac promoter and define the minimal tissue-specific promoter region, progressive 5'-deletion constructs of a segment extending 1053 base pairs upstream of the major transcription start site were generated and tested for promoter activity in various hematopoietic and nonhematopoietic cell types.@@@@1@49@@oe@16-12-2010 866306005@GENIA Treebank@formal@@1@S@The -1053/+34 construct allowed promoter activity only in cells of hematopoietic origin, and tissue specificity was conserved in all other constructs tested.@@@@1@24@@oe@16-12-2010 866306006@GENIA Treebank@formal@@1@S@The region downstream of -90 appeared critical for basal promoter activity.@@@@1@12@@oe@16-12-2010 866306007@GENIA Treebank@formal@@1@S@It contains two potential Ets binding sites conserved in the murine gammac promoter gene, one of which was found essential for functional promoter activity as determined by mutational analysis.@@@@1@31@@oe@16-12-2010 866306008@GENIA Treebank@formal@@1@S@The functional Ets binding site was found to bind Ets family proteins, principally GA-binding protein and Elf-1 and could be transactivated by GABPalpha and -beta synergistically.@@@@1@28@@oe@16-12-2010 866306009@GENIA Treebank@formal@@1@S@These results indicate that, as already reported for the IL2Rbeta promoter, GA-binding protein is an essential component of gammac basal promoter activity.@@@@1@25@@oe@16-12-2010 866306010@GENIA Treebank@formal@@1@S@Although GABP expression is not restricted to the hematopoietic lineage, its interaction with other specific factors may contribute to the tissue-specific expression of the gammac gene.@@@@1@28@@oe@16-12-2010 866314801@GENIA Treebank@formal@@1@S@A 3' --> 5' XPB helicase defect in repair/transcription factor TFIIH of xeroderma pigmentosum group B affects both DNA repair and transcription.@@@@1@23@@oe@16-12-2010 866314802@GENIA Treebank@formal@@1@S@XPB is a subunit of the basal transcription factor TFIIH, which is also involved in nucleotide excision repair (NER) and potentially in cell cycle regulation.@@@@1@29@@oe@16-12-2010 866314803@GENIA Treebank@formal@@1@S@A frameshift mutation in the 3'-end of the XPB gene is responsible for a concurrence of two disorders: xeroderma pigmentosum (XP) and Cockayne's syndrome (CS).@@@@1@32@@oe@16-12-2010 866314804@GENIA Treebank@formal@@1@S@We have isolated TFIIH from cells derived from a patient (XP11BE) who carries this frameshift mutation (TFIIHmut) and from the mother of this patient (TFIIHwt) to determine the biochemical consequences of the mutation.@@@@1@40@@oe@16-12-2010 866314805@GENIA Treebank@formal@@1@S@Although identical in composition and stoichiometry to TFIIHwt, TFIIHmut shows a reduced 3' --> 5' XPB helicase activity.@@@@1@20@@oe@16-12-2010 866314806@GENIA Treebank@formal@@1@S@A decrease in helicase and DNA-dependent ATPase activities was also observed with the mutated recombinant XPB protein.@@@@1@18@@oe@16-12-2010 866314807@GENIA Treebank@formal@@1@S@The XPB mutation causes a severe NER defect.@@@@1@9@@oe@16-12-2010 866314808@GENIA Treebank@formal@@1@S@In addition, we provide evidence for a decrease in basal transcription activity in vitro.@@@@1@16@@oe@16-12-2010 866314809@GENIA Treebank@formal@@1@S@The latter defect may provide an explanation for many of the XP and CS symptoms that are difficult to rationalize based solely on an NER defect.@@@@1@27@@oe@16-12-2010 866314810@GENIA Treebank@formal@@1@S@Thus, this work presents the first detailed analysis of a naturally occurring mutation in a basal transcription factor and supports the concept that the combined XP/CS clinical entity is actually the result of a combined transcription/repair deficiency.@@@@1@39@@oe@16-12-2010 866317401@GENIA Treebank@formal@@1@S@Multiple transcription factors are required for activation of human interleukin 9 gene in T cells.@@@@1@16@@oe@16-12-2010 866317402@GENIA Treebank@formal@@1@S@The genetic elements and regulatory mechanisms responsible for human interleukin 9 (IL-9) gene expression in a human T cell leukemia virus type I-transformed human T cell line, C5MJ2, were investigated.@@@@1@35@@oe@16-12-2010 866317403@GENIA Treebank@formal@@1@S@We demonstrated that IL-9 gene expression is controlled, at least in part, by transcriptional activation.@@@@1@18@@oe@16-12-2010 866317404@GENIA Treebank@formal@@1@S@Transient expression of the luciferase reporter gene linked to serially deleted sequences of the 5'-flanking region of the IL-9 gene has revealed several positive and negative regulatory elements involved in the basal and inducible expression of the IL-9 gene in C5MJ2 cells.@@@@1@43@@oe@16-12-2010 866317405@GENIA Treebank@formal@@1@S@An AP-1 site at -146 to -140 was shown to be involved in the expression of the IL-9 gene.@@@@1@20@@oe@16-12-2010 866317406@GENIA Treebank@formal@@1@S@A proximal region between -46 and -80 was identified as the minimum sequence for the basal and inducible expression of the IL-9 gene in C5MJ2 cells.@@@@1@27@@oe@16-12-2010 866317407@GENIA Treebank@formal@@1@S@Within this region, an NF-kappaB site at -59 to -50 and its adjacent 20-base pair upstream sequence were demonstrated to play a critical role for the IL-9 promoter activity.@@@@1@31@@oe@16-12-2010 866317408@GENIA Treebank@formal@@1@S@DNA-protein binding studies indicated that NF-kappaB, c-Jun, and potentially novel proteins (around 35 kDa) can bind to this important sequence.@@@@1@25@@oe@16-12-2010 866317409@GENIA Treebank@formal@@1@S@Mutations at different sites within this proximal promoter region abolished the promoter activity as well as the DNA binding.@@@@1@20@@oe@16-12-2010 866317410@GENIA Treebank@formal@@1@S@Taken together, these results suggest that the cooperation of different transcription factors is essential for IL-9 gene expression in T cells.@@@@1@23@@oe@16-12-2010 866323001@GENIA Treebank@formal@@1@S@Mapping of the transcriptional repression domain of the lymphoid-specific transcription factor oct-2A.@@@@1@13@@oe@16-12-2010 866323002@GENIA Treebank@formal@@1@S@The lymphoid-specific transcription factor Oct-2a is implicated in B cell-specific transcriptional activity via the octamer motif.@@@@1@17@@oe@16-12-2010 866323003@GENIA Treebank@formal@@1@S@Structure/function analysis of various Oct-2a effector regions in the context of the GAL4 DNA-binding domain revealed that Oct-2a contains two functionally different activation domains at the N and the C termini.@@@@1@32@@oe@16-12-2010 866323004@GENIA Treebank@formal@@1@S@The transcriptional activity of both domains is strongly potentiated by interactions with distinct B cell-specific coactivators.@@@@1@17@@oe@16-12-2010 866323005@GENIA Treebank@formal@@1@S@Recently, we have identified a repression domain located within the N terminus of Oct-2a (amino acids 2-99).@@@@1@21@@oe@16-12-2010 866323006@GENIA Treebank@formal@@1@S@When this domain was transferred to a potent activator, transcription was strongly inhibited.@@@@1@15@@oe@16-12-2010 866323007@GENIA Treebank@formal@@1@S@In this study we present a deletion analysis of the N-terminal region of Oct-2a to determine the minimal repression domain.@@@@1@21@@oe@16-12-2010 866323008@GENIA Treebank@formal@@1@S@We identified a stretch of 23 amino acids, rich in serine and threonine residues, which was responsible for most of the repression activity.@@@@1@26@@oe@16-12-2010 866323009@GENIA Treebank@formal@@1@S@We show that repression is strongly dependent on the type of enhancer present in the reporter plasmid as well as on the cell line tested.@@@@1@26@@oe@16-12-2010 866323010@GENIA Treebank@formal@@1@S@The possibility that Oct-2a can act as an activator and/or a repressor may have important consequences for the function of Oct-2a in B cell differentiation and other developmental processes.@@@@1@30@@oe@16-12-2010 866338001@GENIA Treebank@formal@@1@S@The c-Jun delta-domain inhibits neuroendocrine promoter activity in a DNA sequence- and pituitary-specific manner.@@@@1@15@@oe@16-12-2010 866338002@GENIA Treebank@formal@@1@S@The transcription and transformation activity of c-Jun is governed by a 27-amino acid regulatory motif, labeled the delta-domain, which is deleted in v-Jun.@@@@1@26@@oe@16-12-2010 866338003@GENIA Treebank@formal@@1@S@We have previously shown that c-Jun is a potent inhibitor of the rat prolactin (rPRL) promoter activity induced by either oncogenic Ras or phorbol esters.@@@@1@28@@oe@16-12-2010 866338004@GENIA Treebank@formal@@1@S@Here, we have characterized the structural and cell-specific requirements for this c-Jun inhibitory response, and we show that this c-Jun inhibitory response mapped to the rPRL footprint II repressor site, was pituitary-specific and required the c-Jun delta-domain.@@@@1@41@@oe@16-12-2010 866338005@GENIA Treebank@formal@@1@S@Moreover, alteration of any one of these features (e.g., cis-element, trans-factor, or cell-specific background) switched c-Jun to a transcriptional activator of the rPRL promoter.@@@@1@31@@oe@16-12-2010 866338006@GENIA Treebank@formal@@1@S@In HeLa nonpituitary cells, c-Jun alone activated the rPRL promoter via the most proximal GHF-1/Pit-1 binding site, footprint I, and synergized with GHF-1.@@@@1@27@@oe@16-12-2010 866338007@GENIA Treebank@formal@@1@S@Finally, recombinant GHF-1 interacted directly with c-Jun but not c-Fos proteins.@@@@1@13@@oe@16-12-2010 866338008@GENIA Treebank@formal@@1@S@These data provide important fundamental insights into the molecular mechanisms by which the c-Jun delta-domain functions as a modulatory switch and further imply that the functional role of c-Jun is dictated by cell-specific influences and the delta-domain motif.@@@@1@39@@oe@16-12-2010 866454701@GENIA Treebank@formal@@1@S@The role of BSAP (Pax-5) in B-cell development.@@@@1@11@@oe@16-12-2010 866454702@GENIA Treebank@formal@@1@S@The hierarchy of transcriptional control in B-cell development has recently been analyzed by targeted gene inactivation in the mouse.@@@@1@20@@oe@16-12-2010 866454703@GENIA Treebank@formal@@1@S@In this manner, the paired box containing gene Pax-5, encoding the B cell specific transcription factor BSAP, has been shown to play a key role in early B lymphopoiesis.@@@@1@33@@oe@16-12-2010 866454704@GENIA Treebank@formal@@1@S@Other experimental strategies have implicated BSAP in the control of cell proliferation, isotype switching and transcription of the immunoglobulin heavy-chain gene at late stages of B-cell differentiation.@@@@1@29@@oe@16-12-2010 866678301@GENIA Treebank@formal@@1@S@Modulation of the expression of the IFN-gamma receptor beta-chain controls responsiveness to IFN-gamma in human peripheral blood T cells.@@@@1@20@@oe@16-12-2010 866678302@GENIA Treebank@formal@@1@S@IFN-gamma has potent antiproliferative and apoptotic effects in T cells that are important in determining T cell development and polarized differentiation.@@@@1@22@@oe@16-12-2010 866678303@GENIA Treebank@formal@@1@S@Therefore, any event that enables T cells to become less responsive to IFN- gamma may potentially alter immune responsiveness to Ag.@@@@1@22@@oe@16-12-2010 866678304@GENIA Treebank@formal@@1@S@In this work, we show that human peripheral blood T cells that are stimulated through the TCR and expanded with IL-2 are unresponsive to IFN-gamma, as determined by a lack of activation of jak kinases and the transcription factor, STAT1(alpha), a signal transducer and activator of transcription.@@@@1@52@@oe@16-12-2010 866678305@GENIA Treebank@formal@@1@S@This nonresponsiveness occurs because of a lack of expression of the beta- chain (accessory factor) of the IFN-gamma receptor, while at the same time maintaining IFN-gamma receptor alpha-chain expression.@@@@1@32@@oe@16-12-2010 866678306@GENIA Treebank@formal@@1@S@Expression of the beta-chain can be restored by secondary TCR ligation or PMA treatment.@@@@1@15@@oe@16-12-2010 866678307@GENIA Treebank@formal@@1@S@T cell blasts treated with PMA are now responsive to IFN-gamma.@@@@1@12@@oe@16-12-2010 866678308@GENIA Treebank@formal@@1@S@When freshly isolated, highly enriched (>98%) T cells are examined for IFN-gamma responsiveness; these cells can respond to IFN-gamma and express beta-chain.@@@@1@29@@oe@16-12-2010 866678309@GENIA Treebank@formal@@1@S@Therefore, as T cells progress from primary TCR activation through IL-2-dependent proliferation, followed by secondary TCR stimulation, their responsiveness to IFN-gamma varies, and this may affect their ability to participate in an ongoing immune response.@@@@1@40@@oe@16-12-2010 866679501@GENIA Treebank@formal@@1@S@Induction of CIITA and modification of in vivo HLA-DR promoter occupancy in normal thymic epithelial cells treated with IFN-gamma: similarities and distinctions with respect to HLA-DR-constitutive B cells.@@@@1@30@@oe@16-12-2010 866679502@GENIA Treebank@formal@@1@S@In this study, the IFN-gamma induction of MHC class II gene expression in primary cultures of thymic epithelial cells (TEC) was analyzed.@@@@1@26@@oe@16-12-2010 866679503@GENIA Treebank@formal@@1@S@This cellular system offers the advantage that MHC class II induction is studied in a "physiologic" cell lineage that, as a result of this expression within the thymus, is thought to participate to the selection and maturation of the T cells.@@@@1@46@@oe@16-12-2010 866679504@GENIA Treebank@formal@@1@S@It was found that the MHC class II gene expression was associated with the de novo transcription of the gene encoding the CIITA trans-activator, a crucial MHC class II gene regulatory factor.@@@@1@34@@oe@16-12-2010 866679505@GENIA Treebank@formal@@1@S@Furthermore, the anatomy of interaction between the MHC class II DRA promoter and corresponding binding factors was analyzed by in vivo DNAse I footprint.@@@@1@26@@oe@16-12-2010 866679506@GENIA Treebank@formal@@1@S@It was found that treatment with IFN-gamma induces changes in the occupancy of the DRA gene regulatory sequences by nuclear factors.@@@@1@22@@oe@16-12-2010 866679507@GENIA Treebank@formal@@1@S@The resulting occupancy displays strong similarities with the one observed in the MHC class II-constitutive B cells, represented by both the Burkitt lymphoma line Raji and normal tonsil- derived B cells.@@@@1@32@@oe@16-12-2010 866679508@GENIA Treebank@formal@@1@S@However, some peculiar differences were observed between the TEC, either IFN-gamma-induced or not, and the constitutive B cells.@@@@1@22@@oe@16-12-2010 866679509@GENIA Treebank@formal@@1@S@These results suggest that both common mechanisms, such as the one mediated by the CIITA trans-activator, and distinct tissue-specific constraints contribute to the transcriptional control of constitutive and IFN-gamma-induced MHC class II gene expression.@@@@1@37@@oe@16-12-2010 866681201@GENIA Treebank@formal@@1@S@Antisense inhibition of vitamin D receptor expression induces apoptosis in monoblastoid U937 cells.@@@@1@14@@oe@16-12-2010 866681202@GENIA Treebank@formal@@1@S@The active vitamin D3 metabolite 1,25-dihydroxycholecalciferol (1,25(OH)2D3) acts as an antiproliferative and differentiating agent for the monoblastoid cell line U937 and as an important immunologic mediator implicated particularly in the function of cells belonging to the monocyte/macrophage lineage.@@@@1@41@@oe@16-12-2010 866681203@GENIA Treebank@formal@@1@S@These effects are controlled by the vitamin D receptor (VDR), a member of the steroid hormone receptor family.@@@@1@22@@oe@16-12-2010 866681204@GENIA Treebank@formal@@1@S@The objective of this study was to develop U937 transfectants expressing antisense VDR mRNA, and to use these to examine the role of 1,25(OH)2D3-VDR interaction in this lineage.@@@@1@30@@oe@16-12-2010 866681205@GENIA Treebank@formal@@1@S@A 2-kb VDR cDNA insert (including the complete VDR coding region) was cloned in an antisense orientation into the EBV episomal vector pMEP4 under the control of an inducible promoter and transfected into U937.@@@@1@37@@oe@16-12-2010 866681206@GENIA Treebank@formal@@1@S@The resultant cell line, DH42, was hygromycin resistant, contained VDR cDNA, expressed fewer VDRs than controls, and showed a substantial decrease in antiproliferative response to 1,25(OH)2D3.@@@@1@32@@oe@16-12-2010 866681207@GENIA Treebank@formal@@1@S@However, 1,25(OH)2D3 increased the number of cells expressing macrophage cell surface Ags, including CD14 and CD11b.@@@@1@19@@oe@16-12-2010 866681208@GENIA Treebank@formal@@1@S@A subpopulation of smaller cells did not express the differentiation markers after cadmium stimulation.@@@@1@15@@oe@16-12-2010 866681209@GENIA Treebank@formal@@1@S@Cell cycle analysis showed shifts in the distribution of cells from G1 to S phase, which were more pronounced after cadmium treatment.@@@@1@24@@oe@16-12-2010 866681210@GENIA Treebank@formal@@1@S@A considerable proportion of cells were outside the cycle and DNA fragmentation confirmed apoptosis.@@@@1@15@@oe@16-12-2010 866681211@GENIA Treebank@formal@@1@S@Thus, the functional outcome of the VDR antisense transfection suggests that in the myelomonocytic lineage, VDR expression may act as a protective mechanism against programmed cell death.@@@@1@30@@oe@16-12-2010 866681601@GENIA Treebank@formal@@1@S@Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes.@@@@1@15@@oe@16-12-2010 866681602@GENIA Treebank@formal@@1@S@Eosinophils and neutrophils are closely related, terminally differentiated cells that in vitro undergo constitutive cell death by apoptosis.@@@@1@20@@oe@16-12-2010 866681603@GENIA Treebank@formal@@1@S@The onset of apoptosis in both cell types can be delayed by hemopoietins and inflammatory mediators.@@@@1@17@@oe@16-12-2010 866681604@GENIA Treebank@formal@@1@S@Although there have been a number of reports demonstrating that glucocorticoids (in particular dexamethasone) antagonize the eosinophil life-prolonging effects of hemopoietins, direct effects of dexamethasone on eosinophil apoptosis have not been documented.@@@@1@36@@oe@16-12-2010 866681605@GENIA Treebank@formal@@1@S@In this study we examined the direct effects of glucocorticoids on eosinophil and neutrophil apoptosis in light of their common therapeutic use as anti-inflammatory and anti-allergic/hypereosinophilic agents.@@@@1@28@@oe@16-12-2010 866681606@GENIA Treebank@formal@@1@S@We found that treatment with dexamethasone induced eosinophil apoptosis.@@@@1@10@@oe@16-12-2010 866681607@GENIA Treebank@formal@@1@S@In contrast, dexamethasone was a potent inhibitor of neutrophil apoptosis.@@@@1@12@@oe@16-12-2010 866681608@GENIA Treebank@formal@@1@S@The effect of dexamethasone on both cell types was mediated through the glucocorticoid receptor, i.e., it was abolished by the glucocorticoid receptor antagonist RU38486.@@@@1@27@@oe@16-12-2010 866681609@GENIA Treebank@formal@@1@S@This is the first description of an agent that promotes eosinophil apoptosis while inhibiting neutrophil apoptosis, and thus presents a novel approach to the study of control of apoptosis in these closely related cell types as well as increases our understanding of the clinical action of glucocorticoids in inflammation.@@@@1@51@@oe@16-12-2010 866821301@GENIA Treebank@formal@@1@S@Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes.@@@@1@20@@oe@16-12-2010 866821302@GENIA Treebank@formal@@1@S@Transcription factors of the NFAT family play a key role in the transcription of cytokine genes and other genes during the immune response.@@@@1@24@@oe@16-12-2010 866821303@GENIA Treebank@formal@@1@S@We have identified two new isoforms of the transcription factor NFAT1 (previously termed NFATp) that are the predominant isoforms expressed in murine and human T cells.@@@@1@29@@oe@16-12-2010 866821304@GENIA Treebank@formal@@1@S@When expressed in Jurkat T cells, recombinant NFAT1 is regulated, as expected, by the calmodulin-dependent phosphatase calcineurin, and its function is inhibited by the immunosuppressive agent cyclosporin A (CsA).@@@@1@36@@oe@16-12-2010 866821305@GENIA Treebank@formal@@1@S@Transactivation by recombinant NFAT1 in Jurkat T cells requires dual stimulation with ionomycin and phorbol 12-myristate 13-acetate; this activity is potentiated by coexpression of constitutively active calcineurin and is inhibited by CsA.@@@@1@34@@oe@16-12-2010 866821306@GENIA Treebank@formal@@1@S@Immunocytochemical analysis indicates that recombinant NFAT1 localizes in the cytoplasm of transiently transfected T cells and translocates into the nucleus in a CsA-sensitive manner following ionomycin stimulation.@@@@1@28@@oe@16-12-2010 866821307@GENIA Treebank@formal@@1@S@When expressed in COS cells, however, NFAT1 is capable of transactivation, but it is not regulated correctly: its subcellular localization and transcriptional function are not affected by stimulation of the COS cells with ionomycin and phorbol 12-myristate 13-acetate.@@@@1@43@@oe@16-12-2010 866821308@GENIA Treebank@formal@@1@S@Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response.@@@@1@41@@oe@16-12-2010 867026901@GENIA Treebank@formal@@1@S@An alternatively spliced isoform of the Spi-B transcription factor.@@@@1@10@@oe@16-12-2010 867026902@GENIA Treebank@formal@@1@S@Spi-B is an Ets transcription factor related to the oncoprotein Spi-1/PU.1 and highly expressed in B lymphoid cells.@@@@1@19@@oe@16-12-2010 867026903@GENIA Treebank@formal@@1@S@The Ets proteins share a conserved Ets domain that mediates specific DNA binding.@@@@1@14@@oe@16-12-2010 867026904@GENIA Treebank@formal@@1@S@Spi-B binds DNA sequences containing a core 5'-GGAA-3' and activates transcription through this motif.@@@@1@15@@oe@16-12-2010 867026905@GENIA Treebank@formal@@1@S@Up to date, the biological function of Spi-B remains unknown.@@@@1@12@@oe@16-12-2010 867026906@GENIA Treebank@formal@@1@S@Here, we describe the characterization of an alternatively spliced variant of Spi-B, named deltaSpi-B, which has lost the Ets domain.@@@@1@24@@oe@16-12-2010 867026907@GENIA Treebank@formal@@1@S@In B lymphoid cells, deltaspi-B and spi-B mRNAs were present simultaneously in a ratio of around 10%.@@@@1@20@@oe@16-12-2010 867026908@GENIA Treebank@formal@@1@S@DeltaSpi-B product was not able to bind DNA and was recovered in cytoplasmic cellular extracts.@@@@1@16@@oe@16-12-2010 867026909@GENIA Treebank@formal@@1@S@We raise the hypothesis that delta Spi-B might affect Spi-B function by recruiting factors involved in Spi-B activity.@@@@1@19@@oe@16-12-2010 867089701@GENIA Treebank@formal@@1@S@Multiple p21ras effector pathways regulate nuclear factor of activated T cells.@@@@1@12@@oe@16-12-2010 867089702@GENIA Treebank@formal@@1@S@The transcription factor, Nuclear Factor of Activated T cells (NFAT) is a major target for p21ras and calcium signalling pathways in the IL-2 gene and is induced by p21ras signals acting in synergy with calcium/calcineurin signals.@@@@1@40@@oe@16-12-2010 867089703@GENIA Treebank@formal@@1@S@One p21ras effector pathway involves the MAP kinase ERK-2, and we have examined its role in NFAT regulation.@@@@1@20@@oe@16-12-2010 867089704@GENIA Treebank@formal@@1@S@Expression of dominant negative MAPKK-1 prevents NFAT induction.@@@@1@9@@oe@16-12-2010 867089705@GENIA Treebank@formal@@1@S@Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1, but does not substitute for activated p21ras and synergize with calcium/calcineurin signals to induce NFAT.@@@@1@28@@oe@16-12-2010 867089706@GENIA Treebank@formal@@1@S@Expression of dominant negative N17Rac also prevents TCR and p21ras activation of NFAT, but without interfering with the ERK-2 pathway.@@@@1@22@@oe@16-12-2010 867089707@GENIA Treebank@formal@@1@S@The transcriptional activity of the NFAT binding site is mediated by a complex comprising a member of the NFAT group and AP-1 family proteins.@@@@1@25@@oe@16-12-2010 867089708@GENIA Treebank@formal@@1@S@The induction of AP-1 by p21ras also requires Rac-1 function.@@@@1@11@@oe@16-12-2010 867089709@GENIA Treebank@formal@@1@S@Activated Rac-1 could mimic activated p21ras to induce AP-1 but not to induce NFAT.@@@@1@15@@oe@16-12-2010 867089710@GENIA Treebank@formal@@1@S@Moreover, the combination of activated MAPKK-1 and Rac-1 could not substitute for activated p21ras and synergize with calcium signals to induce NFAT.@@@@1@24@@oe@16-12-2010 867089711@GENIA Treebank@formal@@1@S@Thus, p21ras regulation of NFAT in T cells requires the activity of multiple effector pathways including those regulated by MAPKK-1/ERK-2 and Rac-1.@@@@1@24@@oe@16-12-2010 867522801@GENIA Treebank@formal@@1@S@Interleukin 10 induced c-fos expression in human B cells by activation of divergent protein kinases.@@@@1@16@@oe@16-12-2010 867522802@GENIA Treebank@formal@@1@S@IL-10 is a potent mediator of human B cell growth and plasma cell formation.@@@@1@15@@oe@16-12-2010 867522803@GENIA Treebank@formal@@1@S@However, signal transduction of IL-10 in B cells is poorly understood.@@@@1@13@@oe@16-12-2010 867522804@GENIA Treebank@formal@@1@S@In this study the effect of IL-10 on the expression of the protooncogene c-fos was investigated, because Fos plays a potential role in the regulation of B cell proliferation and differentiation.@@@@1@33@@oe@16-12-2010 867522805@GENIA Treebank@formal@@1@S@B cells were purified from buffy coat preparations of healthy blood donors by positive selection using an anti CD20 monoclonal antibody and a MiniMACS separation unit.@@@@1@27@@oe@16-12-2010 867522806@GENIA Treebank@formal@@1@S@B cells were prestimulated with SAC for 48 hrs.@@@@1@10@@oe@16-12-2010 867522807@GENIA Treebank@formal@@1@S@Then, cells were incubated with medium or IL-10 (100 ng/ml) for 10 to 120 min.@@@@1@19@@oe@16-12-2010 867522808@GENIA Treebank@formal@@1@S@RNA was extracted by phenol/chloroform and c-fos expression was analyzed by PCR assisted mRNA assay.@@@@1@16@@oe@16-12-2010 867522809@GENIA Treebank@formal@@1@S@A significant 2-4 fold increase of c-fos expression was observed within 30 min of stimulation with IL-10 (p < 0.01).@@@@1@23@@oe@16-12-2010 867522810@GENIA Treebank@formal@@1@S@After 2 hrs c-fos expression declined to basal levels.@@@@1@10@@oe@16-12-2010 867522811@GENIA Treebank@formal@@1@S@The effect of IL-10 was dose-dependent with a maximum stimulation using 100 ng/ml of IL-10.@@@@1@16@@oe@16-12-2010 867522812@GENIA Treebank@formal@@1@S@The IL-10 effect on c-fos expression was not blocked by polymyxin B.@@@@1@13@@oe@16-12-2010 867522813@GENIA Treebank@formal@@1@S@Using the tyrosine kinase inhibitor genistein (10 microM) a complete inhibition of IL-10 induced c-fos expression was observed.@@@@1@21@@oe@16-12-2010 867522814@GENIA Treebank@formal@@1@S@In addition, H-7 (10 microM), a specific inhibitor of serine/threonine kinases, significantly blocked IL-10 mediated c-fos expression (p < 0.05).@@@@1@28@@oe@16-12-2010 867522815@GENIA Treebank@formal@@1@S@In conclusion, these data show that IL-10 induces c-fos expression in human B-cells by activation of tyrosine and serine/threonine kinases.@@@@1@22@@oe@16-12-2010 867522816@GENIA Treebank@formal@@1@S@Since this is the first report on IL-10 induced signal transduction, these data may help to identify the intracellular mechanisms by which IL-10 stimulates human B-cells.@@@@1@28@@oe@16-12-2010 867558401@GENIA Treebank@formal@@1@S@Glucocorticoids and interferon-alpha in the acquired immunodeficiency syndrome.@@@@1@9@@oe@16-12-2010 867558402@GENIA Treebank@formal@@1@S@Some patients with acquired immunodeficiency syndrome (AIDS) develop glucocorticoid resistance characterized by low receptor affinity (Kd) for glucocorticoids in mononuclear, cells and high values of ACTH and cortisol.@@@@1@34@@oe@16-12-2010 867558403@GENIA Treebank@formal@@1@S@As glucocorticoids regulate interferon-alpha (IFN alpha) production, we hypothesized that IFN alpha, a cytokine produced predominantly by monocytes in AIDS, should be increased in cortisol-resistant AIDS, attributing the lack of cortisol inhibition to IFN alpha production.@@@@1@43@@oe@16-12-2010 867558404@GENIA Treebank@formal@@1@S@Therefore, we examined glucocorticoid receptor characteristics on monocytes by [3H]dexamethasone binding and measured IFN alpha, cortisol, and ACTH in AIDS patients with (AIDS-GR) or without glucocorticoid resistance (AIDS-C) and controls (C).@@@@1@41@@oe@16-12-2010 867558405@GENIA Treebank@formal@@1@S@Monocytes of AIDS-GR patients had a receptor Kd of 10.5 +/- 4.2 nmol/L that was higher than that in the AIDS-C group (2.9 +/- 0.8 nmol/L) and normal subjects (2.0 +/- 0.8 nmol/L; P < 0.01).@@@@1@42@@oe@16-12-2010 867558406@GENIA Treebank@formal@@1@S@IFN alpha levels were increased in the AIDS-GR group (17 +/- 6 vs. 4 +/- 1 U/mL in the AIDS-C group and 2 +/- 0.5 U/mL in the C group; P < 0.01).@@@@1@37@@oe@16-12-2010 867558407@GENIA Treebank@formal@@1@S@Correlations were found between plasma IFN alpha and receptor Kd on monocytes of AIDS-GR (r = 0.77) and between IFN alpha and plasma cortisol in the same group (r = 0.74).@@@@1@36@@oe@16-12-2010 867558408@GENIA Treebank@formal@@1@S@The poly(I)-poly(C)-induced IFN alpha production by monocytes was inhibited by glucocorticoids in the C and AIDS-C groups (approximately 80% inhibition in both groups); the effect was reversed by the receptor antagonist RU-38486.@@@@1@37@@oe@16-12-2010 867558409@GENIA Treebank@formal@@1@S@By contrast, glucocorticoids failed to inhibit IFNalpha production from AIDS-GR monocytes (approximately 20% inhibition).@@@@1@19@@oe@16-12-2010 867558410@GENIA Treebank@formal@@1@S@In conclusion, elevated IFN alpha levels in AIDS-GR may be due to the lack of inhibitory effect of cortisol on IFN alpha production due to cortisol resistance in monocytes.@@@@1@31@@oe@16-12-2010 867607201@GENIA Treebank@formal@@1@S@Binding and cooperative interactions between two B cell-specific transcriptional coactivators.@@@@1@11@@oe@16-12-2010 867607202@GENIA Treebank@formal@@1@S@The class II transactivator (CIITA) and B cell octamer-binding protein 1/octamer-binding factor 1/Oct coactivator from B cells (Bob1/OBF-1/OCA-B) represent two B cell-specific transcriptional coactivators.@@@@1@29@@oe@16-12-2010 867607203@GENIA Treebank@formal@@1@S@CIITA and Bob1 interact with proteins that bind to conserved upstream sequences in promoters of class II major histocompatibility genes and octamer-binding transcription factors Oct-1 and Oct-2, respectively.@@@@1@30@@oe@16-12-2010 867607204@GENIA Treebank@formal@@1@S@Both CIITA and Bob1 increase the expression from the DRA promoter, which is a prototypic class II promoter.@@@@1@20@@oe@16-12-2010 867607205@GENIA Treebank@formal@@1@S@Moreover, in the presence of CIITA, interactions between class II promoters and Bob1 are independent of the octamer-binding site.@@@@1@22@@oe@16-12-2010 867607206@GENIA Treebank@formal@@1@S@Using in vivo and in vitro binding assays, we confirm that Bob1 binds to CIITA.@@@@1@17@@oe@16-12-2010 867607207@GENIA Treebank@formal@@1@S@Thus, CIITA not only activates the expression of class II genes but recruits another B cell-specific coactivator to increase transcriptional activity of class II promoters in B cells.@@@@1@30@@oe@16-12-2010 867652101@GENIA Treebank@formal@@1@S@Epstein-Barr virus nuclear antigen 2 and latent membrane protein independently transactivate p53 through induction of NF-kappaB activity.@@@@1@18@@oe@16-12-2010 867652102@GENIA Treebank@formal@@1@S@B-cell immortalization by Epstein-Barr virus (EBV) is dependent on permanent control of the cellular processes which normally regulate cell division and apoptosis, functions possessed by p53 in a number of normal cell types.@@@@1@37@@oe@16-12-2010 867652103@GENIA Treebank@formal@@1@S@In studies initiated to evaluate relationships between EBV latent genes and p53, p53 levels were found to increase approximately 10-fold 4 to 5 days after EBV infection of purified resting human B cells; the induced p53 was transcriptionally active.@@@@1@42@@oe@16-12-2010 867652104@GENIA Treebank@formal@@1@S@Latent membrane protein 1 and, to a lesser extent, EBV nuclear antigen 2 mediated the increase in p53 levels via activation of the NF-kappaB transcription factor.@@@@1@29@@oe@16-12-2010 868310601@GENIA Treebank@formal@@1@S@Differential utilization of Janus kinase-signal transducer activator of transcription signaling pathways in the stimulation of human natural killer cells by IL-2, IL-12, and IFN-alpha.@@@@1@27@@oe@16-12-2010 868310602@GENIA Treebank@formal@@1@S@IL-2-, IL-12-, and IFN-alpha-mediated signaling pathways were analyzed in primary NK cells and in the NK3.3 cell line.@@@@1@21@@oe@16-12-2010 868310603@GENIA Treebank@formal@@1@S@Gel mobility shift and immunoprecipitation analyses revealed that in addition to activating STAT3 (signal transducer and activator of transcription-3) and STAT5, IL-2 induced tyrosine and serine phosphorylation of STAT1 alpha, which formed IFN-gamma-activated sequence-binding complexes by itself and with STAT3.@@@@1@45@@oe@16-12-2010 868310604@GENIA Treebank@formal@@1@S@Although IL-2 and IFN-alpha activated STAT1 alpha and STAT5, IL-2 predominantly activated STAT5, while IFN-alpha predominantly activated STAT1 alpha.@@@@1@22@@oe@16-12-2010 868310605@GENIA Treebank@formal@@1@S@IL-2 induced less STAT1 alpha activation and IFN-alpha induced greater STAT5 activation in NK3.3 cells compared with preactivated primary NK cells.@@@@1@22@@oe@16-12-2010 868310606@GENIA Treebank@formal@@1@S@In NK3.3 cells, IL-2 induced comparable formation of c-fos promoter sis-inducible element IFN-gamma-activated sequence-binding complexes containing STAT3 alone with complexes containing STAT3 and STAT1 alpha, while in preactivated primary NK cells, it preferentially induced complexes containing STAT3 and STAT1 alpha.@@@@1@44@@oe@16-12-2010 868310607@GENIA Treebank@formal@@1@S@Thus, signaling in NK3.3 cells is not always identical with that in primary NK cells.@@@@1@17@@oe@16-12-2010 868310608@GENIA Treebank@formal@@1@S@In contrast to IL-2 and IFN-alpha, IL-12 induced strong tyrosine phosphorylation of STAT4 and variable weak phosphorylation of STAT3.@@@@1@21@@oe@16-12-2010 868310609@GENIA Treebank@formal@@1@S@However, supershift analyses using the c-fos promoter sis-inducible element probe showed that IL-12 activated STAT4, STAT1 alpha, and STAT3, and induced complexes containing STAT4 only, STAT4 with STAT1 alpha, STAT3 with STAT1 alpha, or STAT1 alpha only in preactivated primary NK cells.@@@@1@50@@oe@16-12-2010 868310610@GENIA Treebank@formal@@1@S@STAT1 alpha activation by IL-12 correlated with increased phosphorylation of serine, but not tyrosine.@@@@1@16@@oe@16-12-2010 868310611@GENIA Treebank@formal@@1@S@Finally, IL-2 induced tyrosine phosphorylation of JAK1 and JAK3, while IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells.@@@@1@28@@oe@16-12-2010 868310612@GENIA Treebank@formal@@1@S@Differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2, IL-12, and IFN-alpha may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells.@@@@1@40@@oe@16-12-2010 868311001@GENIA Treebank@formal@@1@S@Sublethal levels of oxidative stress stimulate transcriptional activation of c-jun and suppress IL-2 promoter activation in Jurkat T cells.@@@@1@20@@oe@16-12-2010 868311002@GENIA Treebank@formal@@1@S@Sublethal levels of oxidative stress are well known to alter T cell functional responses, but the underlying mechanisms are unknown.@@@@1@22@@oe@16-12-2010 868311003@GENIA Treebank@formal@@1@S@The current study examined the effects of oxidative stress on transcriptional activities mediated by c-Fos/c-Jun AP-1 and the nuclear factor of activated T cells (NF-AT).@@@@1@28@@oe@16-12-2010 868311004@GENIA Treebank@formal@@1@S@The present results show that Jurkat T cells acutely exposed to micromolar concentrations of H2O2 exhibit substantial increases in AP-1 binding activity and the expression of c-jun but not c-fos mRNA.@@@@1@32@@oe@16-12-2010 868311005@GENIA Treebank@formal@@1@S@The preferential induction of c-jun by H2O2 did not represent redox stabilization of mRNA transcripts, and oxidative signals closely resembled PHA/PMA stimulation by effectively transactivating the full length c-jun promoter via the proximal jun1 tumor promoter-responsive element (TRE)-like promoter element.@@@@1@45@@oe@16-12-2010 868311006@GENIA Treebank@formal@@1@S@Similarly, the complexes binding the consensus AP-1 TRE and jun TRE-like motifs in cells exposed to oxidative signals or PHA/PMA were indistinguishable, being composed of c-Fos, c-Jun, and JunD.@@@@1@34@@oe@16-12-2010 868311007@GENIA Treebank@formal@@1@S@However, PHA/PMA but not oxidative signals induced the coordinate activation of reporter constructs containing the AP-1-TRE, NF-AT, and IL-2 promoter regions along with IL-2 mRNA expression.@@@@1@30@@oe@16-12-2010 868311008@GENIA Treebank@formal@@1@S@Furthermore, sublethal levels of H2O2 actively suppressed the transcriptional activation of NF-AT and IL-2 reporters as well as the expression of IL-2 mRNA in cells stimulated with PHA/PMA.@@@@1@30@@oe@16-12-2010 868311009@GENIA Treebank@formal@@1@S@Gel shift analysis revealed that oxidative suppression of NF-AT represented inhibition in the early generation of NFAT complexes rather than the binding of preformed NF-AT complexes.@@@@1@27@@oe@16-12-2010 868311010@GENIA Treebank@formal@@1@S@These results suggest that oxidative signals can positively and negatively regulate T cell transcriptional events and that changes in cellular redox can uncouple AP-1 regulation of c-jun from transcriptional up-regulation of IL-2 via NF-AT.@@@@1@35@@oe@16-12-2010 868742901@GENIA Treebank@formal@@1@S@HIV-1 tat induces the expression of a new hematopoietic cell-specific transcription factor and downregulates MIP-1 alpha gene expression in activated T-cells.@@@@1@22@@oe@16-12-2010 868742902@GENIA Treebank@formal@@1@S@MIP-1 alpha is a secreted chemokine which can inhibit hematopoietic stem cells and modulate inflammatory responses.@@@@1@17@@oe@16-12-2010 868742903@GENIA Treebank@formal@@1@S@It is also an inhibitor of HIV replication in CD8+ T-cells.@@@@1@12@@oe@16-12-2010 868742904@GENIA Treebank@formal@@1@S@The expression of MIP-1 alpha is induced during cellular activation of CD4+ T-cells and monocytes.@@@@1@16@@oe@16-12-2010 868742905@GENIA Treebank@formal@@1@S@It is also expressed in transformed B-cells.@@@@1@8@@oe@16-12-2010 868742906@GENIA Treebank@formal@@1@S@We have previously identified a new transcription factor family (the MNP family) whose expression is crucial for the induction of MIP-1 alpha transcription during cellular activation and in transformed B cells.@@@@1@34@@oe@16-12-2010 868742907@GENIA Treebank@formal@@1@S@Monocytes and transformed B-cells normally express MNP-1 strongly and MNP-2 weakly, while T-cells strongly express only MNP-2.@@@@1@19@@oe@16-12-2010 868742908@GENIA Treebank@formal@@1@S@Recently, we reported that HIV-1 tat downregulates MIP-1 alpha expression in Jurkat T-cells.@@@@1@15@@oe@16-12-2010 868742909@GENIA Treebank@formal@@1@S@In this report we show induction of MNP-1 in Jurkat T-cells expressing HIV-1 tat.@@@@1@15@@oe@16-12-2010 868742910@GENIA Treebank@formal@@1@S@Expression of neither HTLV-1 tax in Jurkat T-cells nor EBV in B-cells had any effect on MNP-1 or MNP-2 expression, showing that the effect is specific for HIV-1 tat.@@@@1@31@@oe@16-12-2010 868742911@GENIA Treebank@formal@@1@S@We propose that HIV-1 tat may inhibit MIP-1 alpha expression by inducing MNP-1 expression in T-cells, probably by either competing with MNP-2 for binding to the MIP-1 alpha promoter or by sequestering it into inactive forms.@@@@1@38@@oe@16-12-2010 869090001@GENIA Treebank@formal@@1@S@IL-10 inhibits nuclear factor-kappa B/Rel nuclear activity in CD3-stimulated human peripheral T lymphocytes.@@@@1@14@@oe@16-12-2010 869090002@GENIA Treebank@formal@@1@S@IL-10 markedly reduces nuclear factor (NF)-kappa B/Rel nuclear activity induced in PBMC by stimulation with the anti-CD3 mAb OKT3.@@@@1@23@@oe@16-12-2010 869090003@GENIA Treebank@formal@@1@S@The inhibition is exerted specifically on the NF-kappa B/Rel activation induced by mAb OKT3, and not that produced by PMA.@@@@1@22@@oe@16-12-2010 869090004@GENIA Treebank@formal@@1@S@As judged by supershifting the DNA-protein complexes with Abs recognizing specific components of the NF-kappa B/Rel protein family, the p50/p65 (Rel A) heterodimeric form of NF-kappa B is primarily affected.@@@@1@34@@oe@16-12-2010 869090005@GENIA Treebank@formal@@1@S@The maximal effect is observed at the IL-10 concentration of 20 U/ml.@@@@1@13@@oe@16-12-2010 869090006@GENIA Treebank@formal@@1@S@IL-10 inhibitory activity is exerted on T lymphocytes and is mediated by monocytes.@@@@1@14@@oe@16-12-2010 869090007@GENIA Treebank@formal@@1@S@Indeed, monocytes pretreated with IL-10 are able so inhibit NF-kappa B nuclear activity in purified T lymphocytes stimulated with OKT3.@@@@1@22@@oe@16-12-2010 869090008@GENIA Treebank@formal@@1@S@Soluble factors do not appear to be involved in the mechanism of inhibition.@@@@1@14@@oe@16-12-2010 869090009@GENIA Treebank@formal@@1@S@On the other hand, the up-regulation of CD80 Ag, found on monocytes obtained from PBMC incubated with OKT3, is not detected after addition of IL-10, and the anti-CD28 mAb CLB-CD28/1 restores the NF-kappa B/Rel nuclear activity in IL-10-inhibited lymphocytes.@@@@1@44@@oe@16-12-2010 869090010@GENIA Treebank@formal@@1@S@Therefore, the NF-kappa B/Rel inhibition might be ascribed to a lack of cooperation between accessory cells and T lymphocytes, resulting from down-regulation of a costimulatory molecule, such as CD80, produced by IL-10 on activated monocytes.@@@@1@40@@oe@16-12-2010 869090011@GENIA Treebank@formal@@1@S@Our results demonstrate that IL-10 can inhibit the induction of NF-kappa B/Rel nuclear activity in CD3-stimulated T lymphocytes.@@@@1@19@@oe@16-12-2010 869090012@GENIA Treebank@formal@@1@S@Since inappropriate activation of kappa B-driven genes has a physiopathologic role in a number of diseases, such as HIV infection, our findings support the possibility of using this cytokine to suppress an undesirable activation of these transcription factors.@@@@1@41@@oe@16-12-2010 869112301@GENIA Treebank@formal@@1@S@Activation protein 1-dependent transcriptional activation of interleukin 2 gene by Ca2+/calmodulin kinase type IV/Gr.@@@@1@15@@oe@16-12-2010 869112302@GENIA Treebank@formal@@1@S@The Ca2+/calmodulin-dependent protein kinase (CaMK) type IV/Gr is selectively expressed in T lymphocytes and is activated after signaling via the T cell antigen receptor (TCR), indicating that it mediates some of the Ca(2+)-dependent transcriptional events that follow TCR engagement.@@@@1@45@@oe@16-12-2010 869112303@GENIA Treebank@formal@@1@S@Here we show that CaMKIV/Gr induces the transcription factor activation protein 1 (AP-1) alone or in synergy with T cell mitogens and with the p21ras oncoprotein.@@@@1@29@@oe@16-12-2010 869112304@GENIA Treebank@formal@@1@S@CaMKIV/ Gr signaling is associated with transcriptional activation of c-fos but is independent of p21ras or calcineurin.@@@@1@18@@oe@16-12-2010 869112305@GENIA Treebank@formal@@1@S@AP-1 is an integral component of the nuclear factor of activated T cells (NFAT) transcriptional complex, which is required for interleukin 2 gene expression in T cells.@@@@1@31@@oe@16-12-2010 869112306@GENIA Treebank@formal@@1@S@We demonstrate that CaMKIV/Gr reconstitutes the capacity of the cytosolic component of NFAT to direct transcription from NFAT sites in non-T cells.@@@@1@23@@oe@16-12-2010 869112307@GENIA Treebank@formal@@1@S@These results reveal a central role for CaMKIV/Gr as a Ca(2+)-regulated activator of gene transcription in T lymphocytes.@@@@1@19@@oe@16-12-2010 869112701@GENIA Treebank@formal@@1@S@Mechanisms of transactivation by nuclear factor of activated T cells-1.@@@@1@11@@oe@16-12-2010 869112702@GENIA Treebank@formal@@1@S@Nuclear factor of activated T cells-family proteins (NFAT1/NFATp, NFATc, NFAT3, and NFAT4/NFATx/NFATc3) play a key role in the transcription of cytokine genes and other genes during the immune response.@@@@1@35@@oe@16-12-2010 869112703@GENIA Treebank@formal@@1@S@We have defined the mechanisms of transactivation by NFAT1.@@@@1@10@@oe@16-12-2010 869112704@GENIA Treebank@formal@@1@S@NFAT1 possesses two transactivation domains whose sequences are not conserved in the other NFAT-family proteins, and a conserved DNA-binding domain that mediates the recruitment of cooperating nuclear transcription factors even when it is expressed in the absence of other regions of the protein.@@@@1@45@@oe@16-12-2010 869112705@GENIA Treebank@formal@@1@S@The activity of the NH2-terminal transactivation domain is modulated by an adjacent regulatory region that contains several conserved sequence motifs represented only in the NFAT family.@@@@1@27@@oe@16-12-2010 869112706@GENIA Treebank@formal@@1@S@Our results emphasize the multiple levels at which NFAT-dependent transactivation is regulated, and predict significant differences in the architecture of cooperative transcription complexes containing different NFAT-family proteins.@@@@1@29@@oe@16-12-2010 869113501@GENIA Treebank@formal@@1@S@The Ets protein Spi-B is expressed exclusively in B cells and T cells during development.@@@@1@16@@oe@16-12-2010 869113502@GENIA Treebank@formal@@1@S@Spi-B and PU.1 are hematopoietic-specific transcription factors that constitute a subfamily of the Ets family of DNA-binding proteins.@@@@1@19@@oe@16-12-2010 869113503@GENIA Treebank@formal@@1@S@Here we show that contrary to previous reports, PU.1 and Spi-B have very different expression patterns.@@@@1@18@@oe@16-12-2010 869113504@GENIA Treebank@formal@@1@S@PU.1 is expressed at high levels in B cells, mast cells, megakaryocytes, macrophages, neutrophils, and immature erythroid cells and at lower levels in mature erythrocytes.@@@@1@31@@oe@16-12-2010 869113505@GENIA Treebank@formal@@1@S@PU.1 is completely absent from peripheral T cells and most T cell lines based on sensitive RT-PCR assays.@@@@1@19@@oe@16-12-2010 869113506@GENIA Treebank@formal@@1@S@In contrast, Spi-B is expressed exclusively in lymphoid cells and can be detected in early fetal thymus and spleen.@@@@1@21@@oe@16-12-2010 869113507@GENIA Treebank@formal@@1@S@In situ hybridizations of adult murine tissues demonstrate Spi-B mRNA in the medulla of the thymus, the white pulp of the spleen, and the germinal centers of lymph nodes.@@@@1@32@@oe@16-12-2010 869113508@GENIA Treebank@formal@@1@S@Spi-B expression is very abundant in B cells and both Spi-B mRNA and protein are detected in some T cells.@@@@1@21@@oe@16-12-2010 869113509@GENIA Treebank@formal@@1@S@In situ hybridization and Northern blot analysis suggest that Spi-B gene expression increases during B cell maturation and decreases during T cell maturation.@@@@1@24@@oe@16-12-2010 869113510@GENIA Treebank@formal@@1@S@Gel-retardation experiments show that Spi-B can bind to all putative PU.1 binding sites, but do not reveal any preferred Spi-B binding site.@@@@1@24@@oe@16-12-2010 869113511@GENIA Treebank@formal@@1@S@Finally, both PU.1 and Spi-B function as transcriptional activators of the immunoglobulin light-chain enhancer E lambda 2.4 when coexpressed with Pip (PU.1-interaction partner) in NIH-3T3 cells.@@@@1@30@@oe@16-12-2010 869113512@GENIA Treebank@formal@@1@S@Taken together, these data suggest that differences in patterns of expression between Spi-B and PU.1 distinguish the function of each protein during development of the immune system.@@@@1@29@@oe@16-12-2010 869292401@GENIA Treebank@formal@@1@S@BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor.@@@@1@12@@oe@16-12-2010 869292402@GENIA Treebank@formal@@1@S@Approximately 40% of diffuse large cell lymphoma are associated with chromosomal translocations that deregulate the expression of the BCL6 gene by juxtaposing heterologous promoters to the BCL-6 coding domain.@@@@1@31@@oe@16-12-2010 869292403@GENIA Treebank@formal@@1@S@The BCL6 gene encodes a 95-kDa protein containing six C-terminal zinc-finger motifs and an N-terminal POZ domain, suggesting that it may function as a transcription factor.@@@@1@28@@oe@16-12-2010 869292404@GENIA Treebank@formal@@1@S@By using a DNA sequence selected for its ability to bind recombinant BCL-6 in vitro, we show here that BCL-6 is present in DNA-binding complexes in nuclear extracts from various B-cell lines.@@@@1@34@@oe@16-12-2010 869292405@GENIA Treebank@formal@@1@S@In transient transfectin experiments, BCL6 can repress transcription from promoters linked to its DNA target sequence and this activity is dependent upon specific DNA-binding and the presence of an intact N-terminal half of the protein.@@@@1@37@@oe@16-12-2010 869292406@GENIA Treebank@formal@@1@S@We demonstrate that this part of the BCL6 molecule contains an autonomous transrepressor domain and that two noncontiguous regions, including the POZ motif, mediate maximum transrepressive activity.@@@@1@30@@oe@16-12-2010 869292407@GENIA Treebank@formal@@1@S@These results indicate that the BCL-6 protein can function as a sequence-specific transcriptional repressor and have implications for the role of BCL6 in normal lymphoid development and lymphomagenesis.@@@@1@29@@oe@16-12-2010 869329601@GENIA Treebank@formal@@1@S@Signals leading to the activation of NF-kappa B transcription factor are stronger in neonatal than adult T lymphocytes.@@@@1@19@@oe@16-12-2010 869329602@GENIA Treebank@formal@@1@S@The molecular background of the defects in the immune reactivity of human neonates has not been fully elucidated.@@@@1@19@@oe@16-12-2010 869329603@GENIA Treebank@formal@@1@S@As the NF-kappa B transcription factor has a central role in the control of transcription of several genes involved in immune and inflammatory responses, the authors have analysed the activation of NF-kappa B in human umbilical cord T lymphocytes.@@@@1@41@@oe@16-12-2010 869329604@GENIA Treebank@formal@@1@S@The activity was tested by quantitating the nuclear proteins binding to an oligonucleotide containing the consensus kappa B binding sequence (electrophoretic mobility shift assay).@@@@1@27@@oe@16-12-2010 869329605@GENIA Treebank@formal@@1@S@The data obtained demonstrate that phorbol dibutyrate/calcium ionophore A23187 (PDBu/iono) combination induced a clearly higher nuclear translocation of NF-kappa B in neonatal than adult T cells.@@@@1@29@@oe@16-12-2010 869329606@GENIA Treebank@formal@@1@S@This higher NF-kappa B activity was restricted to the CD4+ T-cell subset.@@@@1@13@@oe@16-12-2010 869329607@GENIA Treebank@formal@@1@S@Analysis of the nuclear extracts with antibodies directed against the major components of NF-kappa B the p50 and RelA (p65) proteins, indicated that the composition of NF-kappa B was similar in neonatal and adult cells.@@@@1@39@@oe@16-12-2010 869329608@GENIA Treebank@formal@@1@S@These results suggest that neonatal T cells are exposed to oxidative stress-inducing signals during delivery and/or are inherently more sensitive to NF-kappa B activating signals than adult T cells.@@@@1@30@@oe@16-12-2010 869580001@GENIA Treebank@formal@@1@S@Characterization of Grb2-binding proteins in human platelets activated by Fc gamma RIIA cross-linking.@@@@1@14@@oe@16-12-2010 869580002@GENIA Treebank@formal@@1@S@Glutathione-S-transferase (GST)-Grb2 fusion proteins have been used to identify the potential role of Grb2-binding proteins in platelet activation by the platelet low-affinity IgG receptor, Fc gamma RIIA.@@@@1@32@@oe@16-12-2010 869580003@GENIA Treebank@formal@@1@S@Two tyrosine phosphoproteins of 38 and 63 kD bind to the SH2 domain of Grb2 following Fc gamma RIIA stimulation of platelets.@@@@1@23@@oe@16-12-2010 869580004@GENIA Treebank@formal@@1@S@Both are located in the particulate fraction following platelet activation and are also able to bind to a GST-construct containing the SH2 and SH3 domains of phospholipase C gamma 1.@@@@1@31@@oe@16-12-2010 869580005@GENIA Treebank@formal@@1@S@p38 also forms a complex with the tyrosine kinase csk in stimulated cells and is a substrate for the kinase.@@@@1@21@@oe@16-12-2010 869580006@GENIA Treebank@formal@@1@S@The SH3 domains of Grb2 form a stable complex with SOS1 and two proteins of 75 kD and 120 kD, which undergo tyrosine phosphorylation in Fc gamma RIIA stimulated cells.@@@@1@32@@oe@16-12-2010 869580007@GENIA Treebank@formal@@1@S@The 75-kD protein is recognized by antibodies to SLP-76, which has recently been isolated from T cells and sequenced.@@@@1@21@@oe@16-12-2010 869580008@GENIA Treebank@formal@@1@S@Tyrosine phosphorylation of p38 and p63 is also observed in platelets stimulated by the tyrosine kinase-linked receptor agonist collagen and by the G protein-coupled receptor agonist thrombin, although phosphorylation of SLP-76 is only observed in collagen-stimulated platelets.@@@@1@39@@oe@16-12-2010 869580009@GENIA Treebank@formal@@1@S@p38 and p63 may provide a docking site for Grb2, thereby linking Grb2 SH3-binding proteins SOS1, SLP-76, and p120 to downstream signalling events.@@@@1@27@@oe@16-12-2010 869583801@GENIA Treebank@formal@@1@S@Granulocyte-macrophage colony-stimulating factor preferentially activates the 94-kD STAT5A and an 80-kD STAT5A isoform in human peripheral blood monocytes.@@@@1@19@@oe@16-12-2010 869583802@GENIA Treebank@formal@@1@S@Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces immediate effects in monocytes by activation of the Janus kinase (JAK2) and STAT transcription factor (STAT5) pathway.@@@@1@29@@oe@16-12-2010 869583803@GENIA Treebank@formal@@1@S@Recent studies have identified homologues of STAT5, STAT5A, and STAT5B, as well as lower molecular weight variants of STAT5.@@@@1@23@@oe@16-12-2010 869583804@GENIA Treebank@formal@@1@S@To define the activation of the STAT5 homologues and lower molecular weight variant in human monocytes and monocytes differentiated into macrophages by culture in macrophage-CSF (M-CSF), we measured the GM-CSF induced tyrosine phosphorylation of STAT5A, STAT5B, and any lower molecular weight STAT5 isoforms.@@@@1@49@@oe@16-12-2010 869583805@GENIA Treebank@formal@@1@S@Freshly isolated monocytes expressed 94-kD STAT5A, 92-kD STAT5B, and an 80-kD STAT5A molecule.@@@@1@16@@oe@16-12-2010 869583806@GENIA Treebank@formal@@1@S@Whereas 94-kD STAT5A was clearly tyrosine phosphorylated and bound to the enhancer element, the gamma response region (GRR), of the Fc gamma RI gene, substantially less tyrosine phosphorylated STAT5B bound to the immobilized GRR element.@@@@1@41@@oe@16-12-2010 869583807@GENIA Treebank@formal@@1@S@Macrophages lost their ability to express the 80-kD STAT5A protein, but retained their ability to activate STAT5A.@@@@1@19@@oe@16-12-2010 869583808@GENIA Treebank@formal@@1@S@STAT5A-STAT5A homodimers and STAT5A-STAT5B heterodimers formed in response to GM-CSF.@@@@1@11@@oe@16-12-2010 869583809@GENIA Treebank@formal@@1@S@Therefore, activation of STAT5A predominates compared to STAT5B when assayed by direct immunoprecipitation and by evaluation of bound STATs to immobilized GRR.@@@@1@24@@oe@16-12-2010 869583810@GENIA Treebank@formal@@1@S@Selective activation of STAT5 homologues in addition to generation of lower molecular isoforms may provide specificity and control to genes expressed in response to cytokines such as GM-CSF.@@@@1@29@@oe@16-12-2010 869586301@GENIA Treebank@formal@@1@S@LYSP100-associated nuclear domains (LANDs): description of a new class of subnuclear structures and their relationship to PML nuclear bodies.@@@@1@23@@oe@16-12-2010 869586302@GENIA Treebank@formal@@1@S@The PML gene is fused to the retinoic acid receptor alpha (RAR alpha) gene in t(15;17) acute promyelocytic leukemia (APL), creating a PML-RAR alpha fusion oncoprotein.@@@@1@32@@oe@16-12-2010 869586303@GENIA Treebank@formal@@1@S@The PML gene product has been localized to subnuclear dot-like structures variously termed PODs, ND10s, Kr bodies, or PML nuclear bodies (PML NBs).@@@@1@29@@oe@16-12-2010 869586304@GENIA Treebank@formal@@1@S@The present study describes the cloning of a lymphoid-restricted gene, LYSP100, that is homologous to another protein that localizes to PML NBs, SP100.@@@@1@27@@oe@16-12-2010 869586305@GENIA Treebank@formal@@1@S@In addition to SP100 homology regions, one LYSP100 cDNA isoform contains a bromodomain and a PHD/TTC domain, which are present in a variety of transcriptional regulatory proteins.@@@@1@30@@oe@16-12-2010 869586306@GENIA Treebank@formal@@1@S@By immunofluorescence, LYSP100 was localized to nuclear dots that were surprisingly largely nonoverlapping with PML NBs.@@@@1@18@@oe@16-12-2010 869586307@GENIA Treebank@formal@@1@S@However, a minority of LYSP100 nuclear dots exactly colocalized with PML and SP100.@@@@1@15@@oe@16-12-2010 869586308@GENIA Treebank@formal@@1@S@We term the LYSP100 structures "LANDs," for LYSP100-associated nuclear domains.@@@@1@14@@oe@16-12-2010 869586309@GENIA Treebank@formal@@1@S@Although LYSP100 is expressed only in lymphoid cells, LANDs could be visualized in HeLa cells by transfection of a LYSP100 cDNA.@@@@1@23@@oe@16-12-2010 869586310@GENIA Treebank@formal@@1@S@Immunoelectron microscopy revealed LANDs to be globular, electron-dense structures morphologically distinct from the annular structures characteristic of PML NBs.@@@@1@21@@oe@16-12-2010 869586311@GENIA Treebank@formal@@1@S@LANDs were most often found in the nucleoplasm, but were also found at the nuclear membrane and in the cytoplasm, suggesting that these structures may traffic between the cytoplasm and the nucleus.@@@@1@35@@oe@16-12-2010 869586312@GENIA Treebank@formal@@1@S@By double-immunogold labeling of PML and LYSP100, some LANDs were shown to contain both PML and LYSP100.@@@@1@19@@oe@16-12-2010 869586313@GENIA Treebank@formal@@1@S@Thus, PML is localized to a second subnuclear domain that is morphologically and biochemically distinct from PML NBs.@@@@1@20@@oe@16-12-2010 869911801@GENIA Treebank@formal@@1@S@Constitutive expression of specific interferon isotypes in peripheral blood leukocytes from normal individuals and in promonocytic U937 cells.@@@@1@19@@oe@16-12-2010 869911802@GENIA Treebank@formal@@1@S@Constitutive expression of IFN-alpha5 and IFN-beta was detected in different lymphoid cells including peripheral blood mononuclear cells from normal individuals following amplification of IFN mRNA by reverse transcriptase-polymerase chain reaction and direct sequencing of the amplified product.@@@@1@38@@oe@16-12-2010 869911803@GENIA Treebank@formal@@1@S@The activated form of the interferon-induced transcription factor complex ISGF3 was also detected in nuclear extracts from uninduced cells.@@@@1@20@@oe@16-12-2010 869911804@GENIA Treebank@formal@@1@S@Culture supernatants from uninduced U937 cells were also found to activate an ISRE cloned upstream of the luciferase reporter gene, indicating the presence of endogenous IFN activity equivalent to approximately 0.3 to 0.5 IU/mL.@@@@1@36@@oe@16-12-2010 869911805@GENIA Treebank@formal@@1@S@This endogenous IFN was also shown to play a role in maintaining the basal level of expression of the major histocompatibility class I genes in lymphoid cells.@@@@1@28@@oe@16-12-2010 869911806@GENIA Treebank@formal@@1@S@These results suggest that IFN-alpha5 and IFN-beta are produced at low levels in normal tissues and play an important role in the regulation of cell function and in the maintenance of homeostasis.@@@@1@33@@oe@16-12-2010 870022801@GENIA Treebank@formal@@1@S@Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor.@@@@1@11@@oe@16-12-2010 870022802@GENIA Treebank@formal@@1@S@The E2A-HLF (for hepatic leukaemia factor) fusion gene, formed by action of the t(17;19) (q22;p13) chromosomal translocation, drives the leukaemic transformation of early B-cell precursors, but the mechanism of this activity remains unknown.@@@@1@39@@oe@16-12-2010 870022803@GENIA Treebank@formal@@1@S@Here we report that human leukaemia cells carrying the translocation t(17;19) rapidly died by apoptosis when programmed to express a dominant-negative suppressor of the fusion protein E2A-HLF, indicating that the chimaeric oncoprotein probably affects cell survival rather than cell growth.@@@@1@42@@oe@16-12-2010 870022804@GENIA Treebank@formal@@1@S@Moreover, when introduced into murine pro-B lymphocytes, the oncogenic E2A-HLF fusion protein reversed both interleukin-3-dependent and p53-mediated apoptosis.@@@@1@21@@oe@16-12-2010 870022805@GENIA Treebank@formal@@1@S@The close homology of the basic region/leucine zipper (bZIP) DNA-binding and dimerization domain of HLF to that of the CES-2 cell-death specification protein of Caenorhabditis elegans suggests a model of leukaemogenesis in which E2A-HLF blocks an early step within an evolutionarily conserved cell-death pathway.@@@@1@47@@oe@16-12-2010 870246601@GENIA Treebank@formal@@1@S@Protein-tyrosine kinase activation is required for lipopolysaccharide induction of interleukin 1beta and NFkappaB activation, but not NFkappaB nuclear translocation.@@@@1@21@@oe@16-12-2010 870246602@GENIA Treebank@formal@@1@S@In human monocytes, interleukin 1beta protein production and steady state mRNA levels are increased in response to lipopolysaccharide, predominantly as a result of increased transcription of the interleukin 1beta gene.@@@@1@33@@oe@16-12-2010 870246603@GENIA Treebank@formal@@1@S@Expression of interleukin 1beta and other cytokines, such as interleukin 6 and tumor necrosis factor alpha, has been shown to be dependent on the activation of the transcription factor, NFkappaB.@@@@1@34@@oe@16-12-2010 870246604@GENIA Treebank@formal@@1@S@Since recent studies have shown that lipopolysaccharide-induced tyrosine kinase activation is not required for NFkappaB nuclear translocation, we sought to determine whether NFkappaB translocated in the absence of tyrosine kinase activity was active in stimulating transcription.@@@@1@38@@oe@16-12-2010 870246605@GENIA Treebank@formal@@1@S@We have found that, in the human pro-monocytic cell line, THP-1, the lipopolysaccharide-induced expression of interleukin 1beta is dependent on tyrosine kinase activation.@@@@1@27@@oe@16-12-2010 870246606@GENIA Treebank@formal@@1@S@Tyrosine kinases are not required for lipopolysaccharide-mediated nuclear translocation of NFkappaB.@@@@1@12@@oe@16-12-2010 870246607@GENIA Treebank@formal@@1@S@However, in the absence of tyrosine kinase activity, the ability of NFkappaB to stimulate transcription is impaired.@@@@1@20@@oe@16-12-2010 870246608@GENIA Treebank@formal@@1@S@This inhibition of transcription is specific for NFkappaB; in the absence of tyrosine kinase activity, AP-1-dependent transcription is enhanced.@@@@1@22@@oe@16-12-2010 870246609@GENIA Treebank@formal@@1@S@These results suggest that, while lipopolysaccharide-induced expression of inflammatory mediators requires tyrosine kinase activity, tyrosine kinase activity is not obligatory for lipopolysaccharide signal transduction.@@@@1@27@@oe@16-12-2010 870283801@GENIA Treebank@formal@@1@S@Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells.@@@@1@14@@oe@16-12-2010 870283802@GENIA Treebank@formal@@1@S@The NF-kappaB/Rel family of transcription factors regulates the inducible expression of many genes in activated human monocytes and endothelial cells.@@@@1@21@@oe@16-12-2010 870283803@GENIA Treebank@formal@@1@S@In this study, we examined the molecular mechanism by which agents that elevate intracellular cAMP inhibit the expression of the tumor necrosis factor alpha (TNFalpha), tissue factor, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 genes.@@@@1@44@@oe@16-12-2010 870283804@GENIA Treebank@formal@@1@S@Both forskolin and dibutyryl cAMP, which elevate intracellular cAMP by independent mechanisms, inhibited TNFalpha and tissue factor expression at the level of transcription.@@@@1@26@@oe@16-12-2010 870283805@GENIA Treebank@formal@@1@S@Induction of NF-kappaB-dependent gene expression in transiently transfected human monocytic THP-1 cells and human umbilical vein endothelial cells was inhibited by elevated cAMP and by overexpression of the catalytic subunit of protein kinase A (PKA).@@@@1@38@@oe@16-12-2010 870283806@GENIA Treebank@formal@@1@S@Elevated cAMP did not prevent nuclear translocation of p50/p65 and c-Rel/p65 heterodimers, decrease nuclear translocation of p65, or significantly modify TNFalpha-induced phosphorylation of p65.@@@@1@27@@oe@16-12-2010 870283807@GENIA Treebank@formal@@1@S@Functional studies demonstrated that transcriptional activation of a plasmid containing multimerized kappaB sites by p65 was inhibited by agents that elevate cAMP and by overexpression of the catalytic subunit of PKA.@@@@1@32@@oe@16-12-2010 870283808@GENIA Treebank@formal@@1@S@This study indicates that activation of PKA reduces the induction of a distinct set of genes in monocytes and endothelial cells by inhibiting NF-kappaB-mediated transcription.@@@@1@26@@oe@16-12-2010 870284901@GENIA Treebank@formal@@1@S@Characterization of a new isoform of the NFAT (nuclear factor of activated T cells) gene family member NFATc [published erratum appears in J Biol Chem 1996 Dec 27;271(52):33705]@@@@1@39@@oe@16-12-2010 870284902@GENIA Treebank@formal@@1@S@The cyclosporin A (CsA)/FK506-sensitive nuclear factor of activated T cells (NFAT) plays a key role in the inducible expression of cytokine genes in T cells.@@@@1@31@@oe@16-12-2010 870284903@GENIA Treebank@formal@@1@S@Although NFAT has been recently shown to be inducible in several non-T immune cells, the NFAT gene family members characterized to date have been isolated only from T cells.@@@@1@31@@oe@16-12-2010 870284904@GENIA Treebank@formal@@1@S@To further characterize NFAT function in human B cells and to demonstrate cytokine gene specificity of NFAT proteins, we report here the isolation and characterization of a cDNA clone from the Raji B cell line.@@@@1@37@@oe@16-12-2010 870284905@GENIA Treebank@formal@@1@S@The cDNA clone encodes a new isoform, NFATc.beta, of the NFAT gene family member NFATc (designated here NFATc.alpha).@@@@1@23@@oe@16-12-2010 870284906@GENIA Treebank@formal@@1@S@The amino acid sequence of NFATc.beta differs from that of NFATc.alpha in the first NH2-terminal 29 residues and contains an additional region of 142 residues at the COOH terminus.@@@@1@30@@oe@16-12-2010 870284907@GENIA Treebank@formal@@1@S@Northern analysis using a probe encompassing a common region of both isoforms showed two mRNA species of 2.7 and 4.5 kilobase pairs, while an NFATc.beta-specific probe detected only the 4.5-kilobase pair mRNA which was preferentially expressed in the spleen.@@@@1@41@@oe@16-12-2010 870284908@GENIA Treebank@formal@@1@S@Transient expression of NFATc.beta was capable of activating an interleukin-2 NFAT-driven reporter gene in stimulated Jurkat cells in a CsA-sensitive manner.@@@@1@22@@oe@16-12-2010 870284909@GENIA Treebank@formal@@1@S@However, NFATc.beta neither bound to the kappa3 element ( an NFAT-binding site ) in the tumor necrosis factor-alpha promoter nor activated the tumor necrosis factor-alpha promoter in cotransfection assays.@@@@1@31@@oe@16-12-2010 870284910@GENIA Treebank@formal@@1@S@These data suggest that different members or isoforms of NFAT gene family may regulate inducible expression of different cytokine genes.@@@@1@21@@oe@16-12-2010 870416501@GENIA Treebank@formal@@1@S@Retinoic acid activates interferon regulatory factor-1 gene expression in myeloid cells.@@@@1@12@@oe@16-12-2010 870416502@GENIA Treebank@formal@@1@S@All-trans-retinoic acid (ATRA) is the drug of choice in the treatment of acute promyelocytic leukemia (APL).@@@@1@21@@oe@16-12-2010 870416503@GENIA Treebank@formal@@1@S@ATRA induces both in vitro and in vivo differentiation of APL cells into mature granulocytes.@@@@1@16@@oe@16-12-2010 870416504@GENIA Treebank@formal@@1@S@However, the molecular mechanisms involved in ATRA-dependent growth inhibition and cellular differentiation are not presently understood.@@@@1@18@@oe@16-12-2010 870416505@GENIA Treebank@formal@@1@S@The NB4 cell line, which is derived from the bone marrow of a patient with APL during relapse, can be used as a model system to study the growth and differentiation of APL cells.@@@@1@37@@oe@16-12-2010 870416506@GENIA Treebank@formal@@1@S@Because interferon (IFN) regulatory factors (IRF-1 and IRF-2) and other IFN-inducible gene products regulate cell growth, we analyzed the effects of ATRA on the expression of these genes.@@@@1@34@@oe@16-12-2010 870416507@GENIA Treebank@formal@@1@S@We show that ATRA directly activates IRF-1 gene expression, followed by activation of IRF-2 and 2'-5' oligoadenylate synthetase (OAS) gene expression with slower kinetics.@@@@1@28@@oe@16-12-2010 870416508@GENIA Treebank@formal@@1@S@In addition to NB4 cells, ATRA also activated IRF-1 gene expression in HL-60, U937, and THP-1 cells, which all respond to ATRA by growth inhibition.@@@@1@30@@oe@16-12-2010 870416509@GENIA Treebank@formal@@1@S@A more than additive increase in IRF-1 gene expression was seen with ATRA and IFN-gamma in NB4 cells.@@@@1@19@@oe@16-12-2010 870416510@GENIA Treebank@formal@@1@S@ATRA did not activate nuclear factor kappa B or signal transducer and activator of transcription (STAT) activation pathways, suggesting that an alternate mechanism is involved in IRF-1 gene activation.@@@@1@33@@oe@16-12-2010 870416511@GENIA Treebank@formal@@1@S@The ATRA-induced expression of IRF-1, an activator of transcription and repressor of transformation, may be one of the molecular mechanisms of ATRA-induced growth inhibition, and the basis for the synergistic actions of ATRA and IFNs in myeloid leukemia cells.@@@@1@43@@oe@16-12-2010 870744501@GENIA Treebank@formal@@1@S@Cytokine-modulating activity of tepoxalin, a new potential antirheumatic.@@@@1@10@@oe@16-12-2010 870744502@GENIA Treebank@formal@@1@S@Tepoxalin is a new dual cyclooxygenase/5-lipoxygenase anti-inflammatory compound currently under clinical investigation.@@@@1@13@@oe@16-12-2010 870744503@GENIA Treebank@formal@@1@S@It has been shown to possess anti-inflammatory activity in a variety of animal models and more recently to inhibit IL-2 induced signal transduction.@@@@1@24@@oe@16-12-2010 870744504@GENIA Treebank@formal@@1@S@The current study was conducted to evaluate the cytokine modulating activity of tepoxalin and the role of iron in these effects.@@@@1@22@@oe@16-12-2010 870744505@GENIA Treebank@formal@@1@S@In human peripheral blood mononuclear cells (PBMC) stimulated with OKT3/PMA, tepoxalin inhibited lymphocyte proliferation with an IC50 of 6 microM.@@@@1@24@@oe@16-12-2010 870744506@GENIA Treebank@formal@@1@S@Additionally, it inhibited the production of LTB4 (IC50 = 0.5 microM) and the cytokines IL-2, IL-6 and TNF alpha (IC50 = 10-12 microM).@@@@1@30@@oe@16-12-2010 870744507@GENIA Treebank@formal@@1@S@Cytotoxicity was not demonstrated at these concentrations.@@@@1@8@@oe@16-12-2010 870744508@GENIA Treebank@formal@@1@S@Add-back experiments with either cytokines (IL-2 or IL-6), LTB4 or conditioned media failed to restore the proliferative response in the presence of tepoxalin.@@@@1@27@@oe@16-12-2010 870744509@GENIA Treebank@formal@@1@S@However, the concurrent addition of iron (in the form of ferrous or ferric chloride and other iron salts) reversed the inhibition of proliferation caused by tepoxalin.@@@@1@30@@oe@16-12-2010 870744510@GENIA Treebank@formal@@1@S@Tepoxalin also inhibits the activation of NF kappa B, a transcription factor which acts on several cytokine genes.@@@@1@20@@oe@16-12-2010 870744511@GENIA Treebank@formal@@1@S@Tepoxalin's effect on NF kappa B is also reversed by the addition of iron salts.@@@@1@17@@oe@16-12-2010 870744512@GENIA Treebank@formal@@1@S@These data suggest that the action of tepoxalin to inhibit proliferation in PBMC may be at least in part due to its ability to reduce the amount of available iron resulting in decreased activation of NF kappa B and subsequent inhibition of cytokine production.@@@@1@45@@oe@16-12-2010 870919101@GENIA Treebank@formal@@1@S@oriP is essential for EBNA gene promoter activity in Epstein-Barr virus-immortalized lymphoblastoid cell lines.@@@@1@15@@oe@16-12-2010 870919102@GENIA Treebank@formal@@1@S@During Epstein-Barr virus latent infection of B lymphocytes in vitro, six viral nuclear antigens (EBNAs) are expressed from one of two promoters, Cp or Wp, whose activities are mutually exclusive.@@@@1@36@@oe@16-12-2010 870919103@GENIA Treebank@formal@@1@S@Upon infection, Wp is initially active, followed by a switch to Cp for the duration of latency.@@@@1@20@@oe@16-12-2010 870919104@GENIA Treebank@formal@@1@S@In this study, the region upstream of Cp was analyzed for the presence of cis elements involved in regulating the activities of the EBNA gene promoters in established in vitro immortalized lymphoblastoid cell lines (LCLs).@@@@1@39@@oe@16-12-2010 870919105@GENIA Treebank@formal@@1@S@It was determined that oriP, the origin for episomal maintenance during latency, is essential for efficient transcription initiation from either Cp or Wp in LCLs, as well as in some Burkitt's lymphoma cell lines.@@@@1@39@@oe@16-12-2010 870919106@GENIA Treebank@formal@@1@S@Deletion of the EBNA2-dependent enhancer located upstream of Cp resulted in a ca. two- to fivefold reduction in Cp activity in the LCLs assayed.@@@@1@25@@oe@16-12-2010 870919107@GENIA Treebank@formal@@1@S@More extensive deletion of sequences upstream of Cp, including the EBNA2-dependent enhancer, resulted in nearly complete loss of Cp activity.@@@@1@23@@oe@16-12-2010 870919108@GENIA Treebank@formal@@1@S@This loss of activity was shown to correlate with deletion of two CCAAT boxes, a proximal CCAAT box located at bp -61 to -65 and a distal CCAAT box located at bp -253 to -257, upstream of Cp.@@@@1@41@@oe@16-12-2010 870919109@GENIA Treebank@formal@@1@S@Site-directed mutagenesis of these cis elements demonstrated that Cp activity is highly dependent on the presence of a properly positioned CCAAT box, with the dependence on the distal CCAAT box apparent only when the proximal CCAAT box was deleted or mutated.@@@@1@43@@oe@16-12-2010 870919110@GENIA Treebank@formal@@1@S@Deletion of the glucocorticoid response elements located at ca. bp -850 upstream of Cp did not result in a significant loss in activity.@@@@1@24@@oe@16-12-2010 870919111@GENIA Treebank@formal@@1@S@In general, deletions which diminished Cp activity resulted in induction of Wp activity, consistent with suppression of Wp activity by transcriptional interference from Cp.@@@@1@27@@oe@16-12-2010 870919112@GENIA Treebank@formal@@1@S@The identification of oriP and the EBNA2-dependent enhancer as the major positive cis elements involved in regulating Cp activity in LCL suggests that EBNA gene transcription is largely autoregulated by EBNA 1 and EBNA 2.@@@@1@36@@oe@16-12-2010 870920901@GENIA Treebank@formal@@1@S@Various modes of basic helix-loop-helix protein-mediated regulation of murine leukemia virus transcription in lymphoid cell lines.@@@@1@17@@oe@16-12-2010 870920902@GENIA Treebank@formal@@1@S@The transcriptionally regulatory regions of the lymphomagenic Akv and SL3-3 murine leukemia retroviruses (MLVs) contain two types of E-box consensus motifs, CAGATG.@@@@1@26@@oe@16-12-2010 870920903@GENIA Treebank@formal@@1@S@One type, EA/S, is located in the upstream promoter region, and the other, E(gre), is located in a tandem repeat with enhancer properties.@@@@1@29@@oe@16-12-2010 870920904@GENIA Treebank@formal@@1@S@We have examined the requirements of the individual E-boxes in MLV transcriptional regulation.@@@@1@14@@oe@16-12-2010 870920905@GENIA Treebank@formal@@1@S@In lymphoid cell lines only, the E(gre)-binding protein complexes included ALF1 or HEB and E2A basic helix-loop-helix proteins.@@@@1@20@@oe@16-12-2010 870920906@GENIA Treebank@formal@@1@S@Ectopic ALF1 and E2A proteins required intact E(gre) motifs for mediating transcriptional activation.@@@@1@14@@oe@16-12-2010 870920907@GENIA Treebank@formal@@1@S@ALF1 transactivated transcription of Akv MLV through the two E(gre) motifs equally, whereas E2A protein required the promoter-proximal E(gre) motif.@@@@1@22@@oe@16-12-2010 870920908@GENIA Treebank@formal@@1@S@In T- and B-cell lines, the E(gre) motifs were of major importance for Akv MLV transcriptional activity, while the EA/S motif had some effect.@@@@1@27@@oe@16-12-2010 870920909@GENIA Treebank@formal@@1@S@In contrast, neither E(gre) nor EA/S motifs contributed pronouncedly to Akv MLV transcription in NIH 3T3 cells lacking DNA-binding ALF1 or HEB and E2A proteins.@@@@1@27@@oe@16-12-2010 870920910@GENIA Treebank@formal@@1@S@The Id1 protein was found to repress ALF1 activity in vitro and in vivo.@@@@1@15@@oe@16-12-2010 870920911@GENIA Treebank@formal@@1@S@Moreover, ectopic Id1 repressed E(gre)-directed but not EA/S-directed MLV transcription in lymphoid cell lines.@@@@1@16@@oe@16-12-2010 870920912@GENIA Treebank@formal@@1@S@In conclusion, E(gre) motifs and interacting basic helix-loop-helix proteins are important determinants for MLV transcriptional activity in lymphocytic cell lines.@@@@1@22@@oe@16-12-2010 870927801@GENIA Treebank@formal@@1@S@The human T-cell leukemia virus type 1 posttranscriptional trans-activator Rex contains a nuclear export signal.@@@@1@16@@oe@16-12-2010 870927802@GENIA Treebank@formal@@1@S@The Rex protein of human T-cell leukemia virus type 1 is required for the nuclear export of unspliced viral mRNA and, therefore, for virus replication.@@@@1@28@@oe@16-12-2010 870927803@GENIA Treebank@formal@@1@S@In this manuscript, we demonstrate that Rex shuttles between the nucleus and the cytoplasm and that its activation domain constitutes a nuclear export signal that specifies efficient transport to the cytoplasm.@@@@1@33@@oe@16-12-2010 870927804@GENIA Treebank@formal@@1@S@These findings are consistent with a model for Rex-mediated trans-activation in which Rex-viral mRNA complexes are targeted for nuclear export by the direct action of the activation domain.@@@@1@29@@oe@16-12-2010 870963601@GENIA Treebank@formal@@1@S@Effects of IL-10 and IL-4 on LPS-induced transcription factors (AP-1, NF-IL6 and NF-kappa B) which are involved in IL-6 regulation.@@@@1@24@@oe@16-12-2010 870963602@GENIA Treebank@formal@@1@S@Interleukin-10 (IL-10), like IL-4, is known to inhibit cytokine expression in activated human monocytes.@@@@1@19@@oe@16-12-2010 870963603@GENIA Treebank@formal@@1@S@We showed that both IL-10 and IL-4 inhibit LPS-induced IL-6 mRNA and protein expression by inhibiting the transcription rate of the IL-6 gene.@@@@1@24@@oe@16-12-2010 870963604@GENIA Treebank@formal@@1@S@The strong inhibition of the IL-6 transcription rate prompted us to study the effect of IL-10 and IL-4 on the expression of transcription factors.@@@@1@25@@oe@16-12-2010 870963605@GENIA Treebank@formal@@1@S@We questioned whether or not IL-10 and IL-4 affected the expression of transcription factors that are known to be involved in the control of the IL-6 transcription rate, namely activator protein-1 (AP-1), nuclear factor IL-6 (NF-IL6), and nuclear factor kappa B (NF-kappaB).@@@@1@52@@oe@16-12-2010 870963606@GENIA Treebank@formal@@1@S@In electrophoretic mobility shift assays (EMSAs) we showed that IL-10 and IL-4 inhibited LPS-induced AP-1 binding activity.@@@@1@20@@oe@16-12-2010 870963607@GENIA Treebank@formal@@1@S@The inhibiting effect of IL-4 was slightly more pronounced than that of IL-10.@@@@1@14@@oe@16-12-2010 870963608@GENIA Treebank@formal@@1@S@Downregulation of LPS-induced AP-1 was accompanied, and thus possibly explained, by a reduced expression at mRNA level of the two major components of the AP-1 complex, namely c-fos and c-jun as determined by Northern experiments.@@@@1@39@@oe@16-12-2010 870963609@GENIA Treebank@formal@@1@S@Binding activity of NF-IL6 was also strongly inhibited by IL-4 whereas IL-10 showed no effect.@@@@1@16@@oe@16-12-2010 870963610@GENIA Treebank@formal@@1@S@NF-IL6 mRNA levels were not affected by IL-10 or IL-4, suggesting that IL-4 affects binding activity of preexisting NF-IL6.@@@@1@21@@oe@16-12-2010 870963611@GENIA Treebank@formal@@1@S@Neither IL-10 nor IL-4 inhibited LPS-induced NF-kappa B binding activity.@@@@1@11@@oe@16-12-2010 870963612@GENIA Treebank@formal@@1@S@In agreement with this finding, Northern experiments where p65 and p105 mRNA levels were determined, demonstrated that expression of these components of the NF-kappa B transcription factor were not affected by IL-10 or IL-4.@@@@1@37@@oe@16-12-2010 870963613@GENIA Treebank@formal@@1@S@Furthermore, neither IL-10 nor IL-4 showed any effect on I-kappa B mRNA expression as determined by Northern experiments.@@@@1@20@@oe@16-12-2010 870963614@GENIA Treebank@formal@@1@S@Thus, IL-10 and IL-4 similarly affect IL-6 expression.@@@@1@10@@oe@16-12-2010 870963615@GENIA Treebank@formal@@1@S@However, for IL-4 this was accompanied with a reduction of AP-1 and NF-IL6 binding activity whereas IL-10 only inhibited AP-1 binding activity.@@@@1@24@@oe@16-12-2010 870963701@GENIA Treebank@formal@@1@S@Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain.@@@@1@29@@oe@16-12-2010 870963702@GENIA Treebank@formal@@1@S@Interleukin-7 (IL-7) stimulates the proliferation of normal and leukemic B and T cell precursors and T lymphocytes.@@@@1@20@@oe@16-12-2010 870963703@GENIA Treebank@formal@@1@S@Activation of the JAK/STAT pathway has been implicated in IL-7R signaling.@@@@1@12@@oe@16-12-2010 870963704@GENIA Treebank@formal@@1@S@We investigated which STAT complexes are formed upon stimulation of B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells with IL-7.@@@@1@23@@oe@16-12-2010 870963705@GENIA Treebank@formal@@1@S@Gel retardation assays with STAT-binding oligonucleotides showed that IL-7 induces the formation of two major STAT complexes in BCP-ALL cells.@@@@1@21@@oe@16-12-2010 870963706@GENIA Treebank@formal@@1@S@Supershifts with anti-STAT antibodies identified these as STAT1 and STAT5 complexes.@@@@1@12@@oe@16-12-2010 870963707@GENIA Treebank@formal@@1@S@This pattern of STAT activation was seen in all BCP-ALL cases that respond to IL-7 in proliferation assays.@@@@1@19@@oe@16-12-2010 870963708@GENIA Treebank@formal@@1@S@IL-7 also induced STAT/DNA binding in BCP-ALL cases that failed to proliferate in response to IL-7, suggesting that the ability of IL-7R to activate the JAK/STAT pathway per se is not sufficient for proliferation induction.@@@@1@37@@oe@16-12-2010 870963709@GENIA Treebank@formal@@1@S@To determine the contribution of the cytoplasmic domain of the IL-7 receptor alpha chain (IL-7R alpha) to activation of STAT proteins, transfectants of the murine pro-B cell line BAF3 were made that express chimeric receptors consisting of the extracellular domain of human granulocyte colony-stimulating factor receptor (G-CSF-R) and the transmembrane and intracellular domains of human IL-7R alpha.@@@@1@63@@oe@16-12-2010 870963710@GENIA Treebank@formal@@1@S@Activation of the chimeric G-CSF-R/IL-7R alpha with G-CSF resulted in a full proliferative response and induced the phosphorylation of JAK1 but not JAK2.@@@@1@24@@oe@16-12-2010 870963711@GENIA Treebank@formal@@1@S@Major STAT complexes activated by G-CSF-R/IL-7R alpha contained STAT1 or STAT5, while some formation of STAT3-containing complexes was also seen.@@@@1@22@@oe@16-12-2010 870963712@GENIA Treebank@formal@@1@S@These findings establish that STAT1 and STAT5, and possibly STAT3, are activated upon stimulation of precursor B cells with IL-7.@@@@1@23@@oe@16-12-2010 870963713@GENIA Treebank@formal@@1@S@The data further indicate that the IL-7R alpha chains are directly involved in the activation of JAKs and STATs and have a major role in proliferative signaling in precursor B cells.@@@@1@32@@oe@16-12-2010 872338701@GENIA Treebank@formal@@1@S@Gene transcription through activation of G-protein-coupled chemoattractant receptors.@@@@1@9@@oe@16-12-2010 872338702@GENIA Treebank@formal@@1@S@Receptors for leukocyte chemoattractants, including chemokines, are traditionally considered to be responsible for the activation of special leukocyte functions such as chemotaxis, degranulation, and the release of superoxide anions.@@@@1@34@@oe@16-12-2010 872338703@GENIA Treebank@formal@@1@S@Recently, these G-protein-coupled serpentine receptors have been found to transduce signals leading to gene transcription and translation in leukocytes.@@@@1@21@@oe@16-12-2010 872338704@GENIA Treebank@formal@@1@S@Transcription factors, such as NF kappa B and AP-1, are activated upon stimulation of the cells with several chemoattractants at physiologically relevant concentrations.@@@@1@26@@oe@16-12-2010 872338705@GENIA Treebank@formal@@1@S@Activation of transcription factors through these receptors involves G-protein coupling and the activation of protein kinases.@@@@1@17@@oe@16-12-2010 872338706@GENIA Treebank@formal@@1@S@The underlying signaling pathways appear to be different from those utilized by TNF-alpha, a better characterized cytokine that induces the transcription of immediate-early genes.@@@@1@26@@oe@16-12-2010 872338707@GENIA Treebank@formal@@1@S@Chemoattractants stimulate the expression of several inflammatory cytokines and chemokines, which in turn may activate their respective receptors and initiate an autocrine regulatory mechanism for persistent cytokine and chemokine gene expression.@@@@1@33@@oe@16-12-2010 872593901@GENIA Treebank@formal@@1@S@Regulation of gene expression at early stages of B-cell and T-cell differentiation.@@@@1@13@@oe@16-12-2010 872593902@GENIA Treebank@formal@@1@S@The expression of distinct sets of genes at different stages of B-lymphocyte and T-lymphocyte differentiation is controlled at the level of transcription.@@@@1@23@@oe@16-12-2010 872593903@GENIA Treebank@formal@@1@S@A number of recent studies have described interactions between transcription factors in lymphocytes that provide new insights into mechanisms regulating gene expression.@@@@1@23@@oe@16-12-2010 872593904@GENIA Treebank@formal@@1@S@These mechanisms include the assembly of higher order nucleoprotein complexes and other protein-protein interactions that enhance the functional specificity of transcriptional regulators in lymphocytes.@@@@1@25@@oe@16-12-2010 872869401@GENIA Treebank@formal@@1@S@X inactivation analysis in a female with hypomelanosis of Ito associated with a balanced X;17 translocation: evidence for functional disomy of Xp.@@@@1@26@@oe@16-12-2010 872869402@GENIA Treebank@formal@@1@S@X inactivation analysis was performed on normal and hypopigmented skin samples obtained from a female with hypomelanosis of Ito associated with a balanced whole arm X;17 translocation.@@@@1@30@@oe@16-12-2010 872869403@GENIA Treebank@formal@@1@S@Severe skewing of X inactivation resulting in inactivity of the intact X was found in blood and cultures of both types of skin, but analysis of DNA prepared directly from hypopigmented skin showed significant inactivation of the translocated X, inconsistent with the usual mechanism of phenotypic expression in X;autosome translocations.@@@@1@55@@oe@16-12-2010 872869404@GENIA Treebank@formal@@1@S@In addition, dual colour FISH analysis using centromere specific probes for chromosomes X and 17 showed that the breakpoints on both chromosomes lie within the alphoid arrays, making interruption of a locus on either chromosome unlikely.@@@@1@39@@oe@16-12-2010 872869405@GENIA Treebank@formal@@1@S@While partial variable monosomy of loci on chromosome 17p cannot be excluded as contributing to the phenotype in this patient, it is argued that the major likely factor is partial functional disomy of sequences on Xp in cell lineages that have failed to inactivate the intact X chromosome.@@@@1@51@@oe@16-12-2010 873478701@GENIA Treebank@formal@@1@S@Stimulation of the T-cell antigen receptor-CD3 complex signaling pathway by the tyrosine phosphatase inhibitor pervanadate is mediated by inhibition of CD45: evidence for two interconnected Lck/Fyn- or zap-70-dependent signaling pathways.@@@@1@32@@oe@16-12-2010 873478702@GENIA Treebank@formal@@1@S@The tyrosine phosphatase specific inhibitor pervanadate is a potent activator of T lymphocytes through induction of tyrosine phosphorylation and downstream events of the activation cascade.@@@@1@26@@oe@16-12-2010 873478703@GENIA Treebank@formal@@1@S@Using CD45- or CD3-negative variants of the Jurkat leukemic T-cell line we show that the different biochemical events induced by pervanadate appeared to be dependent on the presence at the cell surface of either CD45 or CD3.@@@@1@38@@oe@16-12-2010 873478704@GENIA Treebank@formal@@1@S@CD45-dependent events such as tyrosine phosphorylation of Shc, activation of nuclear factor-kappa B (NF-kappa B), activator protein-1 (AP-1), transcription factors, and stimulation of interleukin-2 (IL-2) promoter and of CD69 and CD25 surface expression paralleled activation of the tyrosine kinases lck and fyn.@@@@1@53@@oe@16-12-2010 873478705@GENIA Treebank@formal@@1@S@By contrast, stimulation of calcium influx, a CD3-dependent event, paralleled zap-70 activation.@@@@1@16@@oe@16-12-2010 873478706@GENIA Treebank@formal@@1@S@The data demonstrate that the T-cell antigen receptor-CD3 (TcR-CD3) complex is functionally linked to two different protein tyrosine kinase (PTK) modules with separate specific functions and that CD45 may be an important regulator of this coupling.@@@@1@41@@oe@16-12-2010 873956301@GENIA Treebank@formal@@1@S@Involvement of tyrosine phosphorylation in endothelial adhesion molecule induction.@@@@1@10@@oe@16-12-2010 873956302@GENIA Treebank@formal@@1@S@Induction of endothelial adhesion molecules by the cytokine tumor necrosis factor-alpha (TNF) can occur independently of protein kinase C and activation of a protein tyrosine kinase (PTK) has recently been implicated in the upregulation of vascular cell adhesion molecule 1 (VCAM-1) by interleukin-4 (IL-4) on endothelial cells.@@@@1@56@@oe@16-12-2010 873956303@GENIA Treebank@formal@@1@S@We demonstrate that the PTK inhibitors herbimycin A or genistein suppress induction of endothelial VCAM-1 and E-selectin, as well as subsequent monocytic cell adhesion to endothelial cells stimulated by TNF.@@@@1@32@@oe@16-12-2010 873956304@GENIA Treebank@formal@@1@S@Inhibition studies indicate that specific tyrosine phosphorylation following PTK activation is involved in the mobilization of the transcription factor, nuclear factor kappa B, and VCAM-1 mRNA expression.@@@@1@30@@oe@16-12-2010 873956305@GENIA Treebank@formal@@1@S@This may have implications for pathophysiological conditions that involve the upregulation of these molecules (e.g. inflammation and atherosclerosis).@@@@1@21@@oe@16-12-2010 874166401@GENIA Treebank@formal@@1@S@[NGFI-B/nur77 family involved in T-cell apoptosis]@@@@1@8@@oe@16-12-2010 874166402@GENIA Treebank@formal@@1@S@NGFI-B/nur77 is a member of the steroid receptor superfamily.@@@@1@10@@oe@16-12-2010 874166403@GENIA Treebank@formal@@1@S@NGFI-B/nur77 and its related genes constitute a family and the NGFI-B/nur77 family consists of three subtypes, named nur77 alpha, nur77 beta, nur77 gamma.@@@@1@27@@oe@16-12-2010 874166404@GENIA Treebank@formal@@1@S@We cloned human nur77 beta cDNA, called TINUR.@@@@1@10@@oe@16-12-2010 874166405@GENIA Treebank@formal@@1@S@Although NGFI-B/nur77 is essential for TCR-mediated apoptosis in T-cell hybridomas, the reports on nur77 knock-out mice and nur77 dominant negative transgenic mice suggest that there is a functional redundancy among NGFI-B/nur77 family.@@@@1@34@@oe@16-12-2010 874166406@GENIA Treebank@formal@@1@S@NGFI-B/nur77 binds to the response element by monomer or heterodimer with retinoid X receptor (RXR).@@@@1@18@@oe@16-12-2010 874166407@GENIA Treebank@formal@@1@S@Assuming that 9-cis-retinoic acid (9-cis-RA) inhibits TCR-mediated apoptosis, nur77 may cause apoptosis by monomer in the absence of 9-cis-RA and may inhibit apoptosis by heterodimer with RXR in the presence of 9-cis-RA.@@@@1@36@@oe@16-12-2010 874708301@GENIA Treebank@formal@@1@S@Transcription specific differences visualized by fluorescence in situ hybridization pattern on interphase nuclei of different cell types.@@@@1@18@@oe@16-12-2010 874708302@GENIA Treebank@formal@@1@S@Application of a "formamide free" and thus "material preserving" in situ hybridization technique using the cDNA of the myf3 gene revealed the following results: Human rhabdomyosarcoma cells, characterized by a high expression of myf3 show intensive hybridization signals in their interphase.@@@@1@48@@oe@16-12-2010 874708303@GENIA Treebank@formal@@1@S@RNase treatment prior to hybridization considerably reduces the size of this signals.@@@@1@13@@oe@16-12-2010 874708304@GENIA Treebank@formal@@1@S@In comparison, isolated nuclei of human lymphocytes in which no need for the expression of this gene exists, show barely hybridization signals.@@@@1@25@@oe@16-12-2010 874708305@GENIA Treebank@formal@@1@S@Correspondingly, RNase treatment had no effect on hybridization pattern at all.@@@@1@13@@oe@16-12-2010 874708306@GENIA Treebank@formal@@1@S@In conclusion an increased transcription efficiency of a cell type specific gene is accompanied by a higher hybridization accessibility in the corresponding cell nuclei.@@@@1@25@@oe@16-12-2010 875193701@GENIA Treebank@formal@@1@S@Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional activator NF-kappa B.@@@@1@32@@oe@16-12-2010 875193702@GENIA Treebank@formal@@1@S@There is increasing evidence that lipoproteins of Treponema pallidum and Borrelia burgdorferi are key inflammatory mediators during syphilis and Lyme disease.@@@@1@22@@oe@16-12-2010 875193703@GENIA Treebank@formal@@1@S@A principal objective of the present study was to identify more precisely similarities and divergences among lipopolysaccharide (LPS)- and lipoprotein-lipopeptide-induced immune cell signaling events.@@@@1@28@@oe@16-12-2010 875193704@GENIA Treebank@formal@@1@S@Like LPS, purified native B. burgdorferi OspA and synthetic analogs of OspA, OspB, and two T. pallidum lipoproteins (Tpp47 and Tpp17) all induced NF-kappa B translocation in THP-1 human monocytoid cells.@@@@1@37@@oe@16-12-2010 875193705@GENIA Treebank@formal@@1@S@Acylation of OspA and the synthetic peptides was requisite for cell activation.@@@@1@13@@oe@16-12-2010 875193706@GENIA Treebank@formal@@1@S@Polymyxin B abrogated only the response to LPS.@@@@1@9@@oe@16-12-2010 875193707@GENIA Treebank@formal@@1@S@By using 70Z/3-derived pre-B-cell lines either lacking or expressing human CD14 (the LPS receptor), it was observed that expression of human CD14 imparted responsiveness to LPS but not to OspA or spirochetal lipopeptides (assessed by induction of NF-kappa B and expression of surface immunoglobulin M).@@@@1@51@@oe@16-12-2010 875193708@GENIA Treebank@formal@@1@S@Finally, the biological relevance of the observation that T. pallidum lipoproteins-lipopeptides induce both NF-kappa B and cytokine production in monocytes was supported by the ability of the synthetic analogs to promote human immunodeficiency virus replication in chronically infected U1 monocytoid cells; these observations also suggest a potential mechanism whereby a syphilitic chancre can serve as a cofactor for human immunodeficiency virus transmission.@@@@1@65@@oe@16-12-2010 875193709@GENIA Treebank@formal@@1@S@The combined data lend additional support to the proposal that spirochetal lipoproteins and LPS initiate monocyte activation via different cell surface events but that the signaling pathways ultimately converge to produce qualitatively similar cellular responses.@@@@1@36@@oe@16-12-2010 875485501@GENIA Treebank@formal@@1@S@Precise alignment of sites required for mu enhancer activation in B cells.@@@@1@13@@oe@16-12-2010 875485502@GENIA Treebank@formal@@1@S@The lymphocyte-specific immunoglobulin mu heavy-chain gene intronic enhancer is regulated by multiple nuclear factors.@@@@1@15@@oe@16-12-2010 875485503@GENIA Treebank@formal@@1@S@The previously defined minimal enhancer containing the muA, muE3, and muB sites is transactivated by a combination of the ETS-domain proteins PU.1 and Ets-1 in nonlymphoid cells.@@@@1@30@@oe@16-12-2010 875485504@GENIA Treebank@formal@@1@S@The core GGAAs of the muA and muB sites are separated by 30 nucleotides, suggesting that ETS proteins bind to these sites from these same side of the DNA helix.@@@@1@32@@oe@16-12-2010 875485505@GENIA Treebank@formal@@1@S@We tested the necessity for appropriate spatial alignment of these elements by using mutated enhancers with altered spacings.@@@@1@19@@oe@16-12-2010 875485506@GENIA Treebank@formal@@1@S@A 4- or 10-bp insertion between muE3 and muB inactivated the mu enhancer in S194 plasma cells but did not affect in vitro binding of Ets-1, PU.1, or the muE3-binding protein TFE3, alone or in pairwise combinations.@@@@1@41@@oe@16-12-2010 875485507@GENIA Treebank@formal@@1@S@Circular permutation and phasing analyses demonstrated that PU.1 binding but not TFE3 or Ets-1 bends mu enhancer DNA toward the major groove.@@@@1@23@@oe@16-12-2010 875485508@GENIA Treebank@formal@@1@S@We propose that the requirement for precise spacing of the muA and muB elements is due in part to a directed DNA bend induced by PU.1.@@@@1@27@@oe@16-12-2010 875556601@GENIA Treebank@formal@@1@S@Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction.@@@@1@14@@oe@16-12-2010 875556602@GENIA Treebank@formal@@1@S@Vaccination with synthetic peptides representing cytotoxic T lymphocyte (CTL) epitopes can lead to a protective CTL-mediated immunity against tumors or viruses.@@@@1@24@@oe@16-12-2010 875556603@GENIA Treebank@formal@@1@S@We now report that vaccination with a CTL epitope derived from the human adenovirus type 5 E1A-region (Ad5E1A234-243), which can serve as a target for tumor-eradicating CTL, enhances rather than inhibits the growth of Ad5E1A-expressing tumors.@@@@1@41@@oe@16-12-2010 875556604@GENIA Treebank@formal@@1@S@This adverse effect of peptide vaccination was rapidly evoked, required low doses of peptide (10 micrograms), and was achieved by a mode of peptide delivery that induces protective T-cell-mediated immunity in other models.@@@@1@38@@oe@16-12-2010 875556605@GENIA Treebank@formal@@1@S@Ad5E1A-specific CTL activity could no longer be isolated from mice after injection of Ad5E1A-peptide, indicating that tolerization of Ad5E1A-specific CTL activity causes the enhanced tumor outgrowth.@@@@1@28@@oe@16-12-2010 875556606@GENIA Treebank@formal@@1@S@In contrast to peptide vaccination, immunization with adenovirus, expressing Ad5E1A, induced Ad5E1A-specific immunity and prevented the outgrowth of Ad5E1A-expressing tumors.@@@@1@24@@oe@16-12-2010 875556607@GENIA Treebank@formal@@1@S@These results show that immunization with synthetic peptides can lead to the elimination of anti-tumor CTL responses.@@@@1@18@@oe@16-12-2010 875556608@GENIA Treebank@formal@@1@S@These findings are important for the design of safe peptide-based vaccines against tumors, allogeneic organ transplants, and T-cell-mediated autoimmune diseases.@@@@1@23@@oe@16-12-2010 875557401@GENIA Treebank@formal@@1@S@Transgenic expression of PML/RARalpha impairs myelopoiesis.@@@@1@7@@oe@16-12-2010 875557402@GENIA Treebank@formal@@1@S@The translocation found in acute promyelocytic leukemia rearranges the promyelocytic leukemia gene (PML) on chromosome 15 with the retinoic acid receptor alpha (RARalpha) on chromosome 17.@@@@1@31@@oe@16-12-2010 875557403@GENIA Treebank@formal@@1@S@This yields a fusion transcript, PML/RARalpha, a transcription factor with reported dominant negative functions in the absence of hormone.@@@@1@22@@oe@16-12-2010 875557404@GENIA Treebank@formal@@1@S@Clinical remissions induced with all-trans retinoic acid (RA) treatment in acute promyelocytic leukemia are linked to PML/RARalpha expression in leukemic cells.@@@@1@24@@oe@16-12-2010 875557405@GENIA Treebank@formal@@1@S@To evaluate the PML/RARalpha role in myelopoiesis, transgenic mice expressing PML/RARalpha were engineered.@@@@1@15@@oe@16-12-2010 875557406@GENIA Treebank@formal@@1@S@A full-length PML/RARalpha cDNA driven by the CD11b promoter was expressed in transgenic mice.@@@@1@15@@oe@16-12-2010 875557407@GENIA Treebank@formal@@1@S@Expression was confirmed in the bone marrow with a reverse transcription PCR assay.@@@@1@14@@oe@16-12-2010 875557408@GENIA Treebank@formal@@1@S@Basal total white blood cell and granulocyte counts did not appreciably differ between PML/RARalpha transgenic and control mice.@@@@1@19@@oe@16-12-2010 875557409@GENIA Treebank@formal@@1@S@Cell sorter analysis of CD11b+ bone marrow cells revealed similar CD11b+ populations in transgenic and control mice.@@@@1@18@@oe@16-12-2010 875557410@GENIA Treebank@formal@@1@S@However, in vitro clonal growth assays performed on peripheral blood from transgenic versus control mice revealed a marked reduction of myeloid progenitors, especially in those responding to granulocyte/ macrophage colony-stimulating factor.@@@@1@33@@oe@16-12-2010 875557411@GENIA Treebank@formal@@1@S@Granulocyte/macrophage colony-stimulating factor and kit ligand cotreatment did not overcome this inhibition.@@@@1@13@@oe@16-12-2010 875557412@GENIA Treebank@formal@@1@S@Impaired myelopoiesis in vivo was shown by stressing these mice with sublethal irradiation.@@@@1@14@@oe@16-12-2010 875557413@GENIA Treebank@formal@@1@S@Following irradiation, PML/RARalpha transgenic mice, as compared with controls, more rapidly depressed peripheral white blood cell and granulocyte counts.@@@@1@23@@oe@16-12-2010 875557414@GENIA Treebank@formal@@1@S@As expected, nearly all control mice (94.4%) survived irradiation, yet this irradiation was lethal to 45.8% of PML/RARalpha transgenic mice.@@@@1@27@@oe@16-12-2010 875557415@GENIA Treebank@formal@@1@S@Lethality was associated with more severe leukopenia in transgenic versus control mice.@@@@1@13@@oe@16-12-2010 875557416@GENIA Treebank@formal@@1@S@Retinoic acid treatment of irradiated PML/RARalpha mice enhanced granulocyte recovery.@@@@1@11@@oe@16-12-2010 875557417@GENIA Treebank@formal@@1@S@These data suggest that abnormal myelopoiesis due to PML/RARalpha expression is an early event in oncogenic transformation.@@@@1@18@@oe@16-12-2010 875662201@GENIA Treebank@formal@@1@S@Interaction of the human T-cell lymphotropic virus type 1 tax transactivator with transcription factor IIA.@@@@1@16@@oe@16-12-2010 875662202@GENIA Treebank@formal@@1@S@The Tax protein of human T-cell lymphotropic virus type 1 (HTLV-1) is a 40-kDa transcriptional activator which is critical for HTLV-1 gene regulation and virus-induced cellular transformation.@@@@1@30@@oe@16-12-2010 875662203@GENIA Treebank@formal@@1@S@Tax is localized to the DNA through its interaction with the site-specific activators cyclic AMP-responsive element-binding protein, NF-kappaB, and serum response factor.@@@@1@25@@oe@16-12-2010 875662204@GENIA Treebank@formal@@1@S@It has been suggested that the recruitment of Tax to the DNA positions Tax for interaction with the basal transcriptional machinery.@@@@1@22@@oe@16-12-2010 875662205@GENIA Treebank@formal@@1@S@On the basis of several independent assays, we now report a physical and functional interaction between Tax and the transcription factor, TFIIA.@@@@1@25@@oe@16-12-2010 875662206@GENIA Treebank@formal@@1@S@First, Tax was found to interact with the 35-kDa (alpha) subunit of TFIIA in the yeast two-hybrid interaction system.@@@@1@23@@oe@16-12-2010 875662207@GENIA Treebank@formal@@1@S@Importantly, two previously characterized mutants with point mutations in Tax, M32 (Y196A, K197S) and M41 (H287A, P288S), which were shown to be defective in Tax-activated transcription were unable to interact with TFIIA in this assay.@@@@1@45@@oe@16-12-2010 875662208@GENIA Treebank@formal@@1@S@Second, a glutathione-S-transferase (GST) affinity-binding assay showed that the interaction of holo-TFIIA with GST-Tax was 20-fold higher than that observed with either the GST-Tax M32 activation mutant or the GST control.@@@@1@35@@oe@16-12-2010 875662209@GENIA Treebank@formal@@1@S@Third, a coimmunoprecipitation assay showed that in HTLV-1-infected human T lymphocytes, Tax and TFIIA were associated.@@@@1@19@@oe@16-12-2010 875662210@GENIA Treebank@formal@@1@S@Finally, TFIIA facilitates Tax transactivation in vitro and in vivo.@@@@1@12@@oe@16-12-2010 875662211@GENIA Treebank@formal@@1@S@In vitro transcription studies showed reduced levels of Tax-activated transcription in cell extracts depleted of TFIIA.@@@@1@17@@oe@16-12-2010 875662212@GENIA Treebank@formal@@1@S@In addition, transfection of human T lymphocytes with TFIIA expression vectors enhanced Tax-activated transcription of an HTLV-1 long terminal repeat-chloramphenicol acetyltransferase reporter construct.@@@@1@25@@oe@16-12-2010 875662213@GENIA Treebank@formal@@1@S@Our study suggests that the interaction of Tax with the transcription factor TFIIA may play a role in Tax-mediated transcriptional activation.@@@@1@22@@oe@16-12-2010 875731601@GENIA Treebank@formal@@1@S@Alpha 4 beta 1 (CD49d/CD29) integrin costimulation of human T cells enhances transcription factor and cytokine induction in the absence of altered sensitivity to anti-CD3 stimulation.@@@@1@29@@oe@16-12-2010 875731602@GENIA Treebank@formal@@1@S@The integrin alpha 4 beta 1 can provide a costimulus to induce IL-2 secretion and IL-2R expression leading to enhanced proliferation of purified, peripheral blood T cells.@@@@1@29@@oe@16-12-2010 875731603@GENIA Treebank@formal@@1@S@Similar to expression of IL-2, we demonstrated that recombinant vascular-cell adhesion molecule-1, when co-immobilized with anti-CD3 mAb, significantly enhanced the induction of transcription factors NF-AT, AP-1, and NF-kappa B as determined by electromobility shift assays.@@@@1@41@@oe@16-12-2010 875731604@GENIA Treebank@formal@@1@S@alpha 4 beta 1 ligation alone had no effect on transcription factor binding.@@@@1@14@@oe@16-12-2010 875731605@GENIA Treebank@formal@@1@S@The requirements for induction of transcription factors reflected the requirements for the secretion of multiple cytokines, including IL-2, TNF-alpha, IFN-gamma, and granulocyte macrophage-CSF.@@@@1@28@@oe@16-12-2010 875731606@GENIA Treebank@formal@@1@S@In contrast to freshly isolated T cells, in vitro-cultured T cells did not require costimulation for cytokine secretion in response to anti-CD3 alone.@@@@1@25@@oe@16-12-2010 875731607@GENIA Treebank@formal@@1@S@Comparison of the dose response to anti-CD3 stimulation demonstrated that half-maximal induction of IL-2 was achieved using the same dose of anti-CD3 for both freshly isolated and cultured T cells.@@@@1@31@@oe@16-12-2010 875731608@GENIA Treebank@formal@@1@S@Furthermore, the dose of OKT3 required to achieve half-maximal activation was the same using PMA or different concentrations of alpha 4 beta 1 ligands.@@@@1@26@@oe@16-12-2010 875731609@GENIA Treebank@formal@@1@S@Therefore, costimulation by alpha 4 beta 1 ligands was not due to stabilization of the interaction of the cells with its substrate.@@@@1@24@@oe@16-12-2010 875731610@GENIA Treebank@formal@@1@S@We conclude, rather, that alpha 4 beta 1 in freshly isolated T cells delivers a distinct signal that synergizes early with signals initiated by TCR/CD3 ligation to induce DNA binding of multiple transcription factors required for cytokine gene induction.@@@@1@42@@oe@16-12-2010 875732601@GENIA Treebank@formal@@1@S@Defective transcription of the IL-2 gene is associated with impaired expression of c-Fos, FosB, and JunB in anergic T helper 1 cells.@@@@1@25@@oe@16-12-2010 875732602@GENIA Treebank@formal@@1@S@Anergic CD4+ Th cells do not produce IL-2 when challenged with Ag-pulsed accessory cells because of a transcriptional defect.@@@@1@20@@oe@16-12-2010 875732603@GENIA Treebank@formal@@1@S@In this work, we report that these anergic T cells are defective in their ability to up-regulate protein binding and transactivation at two critical IL-2 DNA enhancer elements: NF-AT (nuclear factor of activated T cells; a sequence that binds a heterotrimeric NFATp, Fos, and Jun protein complex) and Activator Protein-1 (AP-1) (that binds Fos and Jun heterodimers).@@@@1@69@@oe@16-12-2010 875732604@GENIA Treebank@formal@@1@S@Western blot analysis of nuclear extracts showed that the impaired DNA-protein interactions in anergic T cells were associated with poor expression of the inducible AP-1 family members c-Fos, FosB, and JunB.@@@@1@34@@oe@16-12-2010 875732605@GENIA Treebank@formal@@1@S@However, the reduced expression of these proteins was not the result of a global TCR/CD3-signaling defect because CD3 cross-linking induced an equivalent increase in intracellular-free calcium ions, as well as NFATp dephosphorylation, translocation to the nucleus, and DNA binding in both normal and anergic T cells.@@@@1@51@@oe@16-12-2010 875732606@GENIA Treebank@formal@@1@S@Thus, defective IL-2 gene transcription appears to be due, at least in part, to a selective block in the expression of the AP-1 Fos and Jun family members in anergic T cells.@@@@1@36@@oe@16-12-2010 875760301@GENIA Treebank@formal@@1@S@CTL recognition of an altered peptide associated with asparagine bond rearrangement.@@@@1@12@@oe@16-12-2010 875760302@GENIA Treebank@formal@@1@S@Implications for immunity and vaccine design.@@@@1@7@@oe@16-12-2010 875760303@GENIA Treebank@formal@@1@S@The extent to which peptides containing chemically and post-translationally modified amino acid side chains are recognized by primed CTL has not been clearly defined.@@@@1@25@@oe@16-12-2010 875760304@GENIA Treebank@formal@@1@S@We report on the CTL recognition of a MHC class I-restricted peptide containing a cyclized asparagine (succinimide) residue.@@@@1@21@@oe@16-12-2010 875760305@GENIA Treebank@formal@@1@S@This modification of the asparagine side chain is a common intermediate structure during deamidation, isomerization, and bond rearrangements of amide-containing amino acids and also occurs as a side reaction in peptide synthesis.@@@@1@35@@oe@16-12-2010 875760306@GENIA Treebank@formal@@1@S@The CTL specifically recognized the succinimide-containing peptide showing only weak cross-reactivity at high concentrations of the parent peptide containing unmodified asparagine.@@@@1@22@@oe@16-12-2010 875760307@GENIA Treebank@formal@@1@S@Similarly, CTL raised against the parent peptide did not recognize the succinimide derivative of this peptide.@@@@1@18@@oe@16-12-2010 875760308@GENIA Treebank@formal@@1@S@Naturally processed forms of these structures are likely to occur given the importance and frequency of deamidation both in vitro and in vivo.@@@@1@24@@oe@16-12-2010 875760309@GENIA Treebank@formal@@1@S@Moreover, since succinimide intermediates of deamidated peptides can occasionally be very stable, these peptides have the potential to act as altered self-Ags with significant implications for autoimmunity.@@@@1@30@@oe@16-12-2010 875760310@GENIA Treebank@formal@@1@S@In addition, unwanted and potentially hazardous specificities may be elicited when using synthetic peptides in subunit vaccines in which succinimide residues may form spontaneously during storage or chemical synthesis.@@@@1@31@@oe@16-12-2010 875889801@GENIA Treebank@formal@@1@S@C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines.@@@@1@15@@oe@16-12-2010 875889802@GENIA Treebank@formal@@1@S@Previous work has shown that C/EBP sites and C/EBP transcriptional activators are necessary for HIV-1 LTR activity in monocytes/macrophages.@@@@1@20@@oe@16-12-2010 875889803@GENIA Treebank@formal@@1@S@We have investigated the role that C/EBP proteins play in induction and replication of HIV-1.@@@@1@16@@oe@16-12-2010 875889804@GENIA Treebank@formal@@1@S@Ectopic expression of the dominant negative C/EBP protein LIP inhibited HIV-1 mRNA and virus production in activated U1 cells, demonstrating that C/EBP proteins are required for provirus induction.@@@@1@30@@oe@16-12-2010 875889805@GENIA Treebank@formal@@1@S@U1 lines overexpressing C/EBP activator NF-IL-6 produced more viral mRNA and virus particles following cellular activation than control lines, demonstrating that C/EBP proteins are limiting for virus transcription.@@@@1@30@@oe@16-12-2010 875889806@GENIA Treebank@formal@@1@S@HIV-1 harboring mutations within two C/EBP sites were crippled in their ability to replicate in U937 promonocytic cells, indicating that these sites are required for replication.@@@@1@28@@oe@16-12-2010 875889807@GENIA Treebank@formal@@1@S@These data identify C/EBP proteins as regulators of HIV-1 expression in monocytes/macrophages.@@@@1@13@@oe@16-12-2010 875972101@GENIA Treebank@formal@@1@S@Inhibition of transcription factor Stat1 activity in mononuclear cell cultures and T cells by the cyclic AMP signaling pathway.@@@@1@20@@oe@16-12-2010 875972102@GENIA Treebank@formal@@1@S@Activation of T cells results in a cascade of gene activation and subsequent proliferation and differentiation into effector phenotypes.@@@@1@20@@oe@16-12-2010 875972103@GENIA Treebank@formal@@1@S@The regulation of transcription factors belonging to the signal transducer and activator of transcription (STAT) family was analyzed in PHA-activated mononuclear cells and in purified T cells activated by cross-linking cell surface CD3.@@@@1@36@@oe@16-12-2010 875972104@GENIA Treebank@formal@@1@S@Cell activation resulted in a delayed induction of STAT DNA-binding activity, which was sustained for several days, was composed predominantly of Stat1 and Stat3, and was blocked by cycloheximide and actinomycin D.@@@@1@36@@oe@16-12-2010 875972105@GENIA Treebank@formal@@1@S@Increased Stat1 and Stat3 mRNA and protein levels were detected, respectively 4 and 24 h after activation.@@@@1@19@@oe@16-12-2010 875972106@GENIA Treebank@formal@@1@S@Stimulation of the cAMP signal transduction pathway, which skews cytokine production toward a Th2 pattern, resulted in the preferential suppression of Stat1 activity.@@@@1@26@@oe@16-12-2010 875972107@GENIA Treebank@formal@@1@S@cAMP inhibited the induction of expression of IL-2 receptor components, but did not inhibit IL-4 receptor alpha-chain and CD69 expression or the induction of activator protein 1 transcription factors.@@@@1@31@@oe@16-12-2010 875972108@GENIA Treebank@formal@@1@S@cAMP signaling inhibited Stat1 at several different levels, including suppression of DNA binding and down-regulation of Stat1 protein and mRNA levels.@@@@1@23@@oe@16-12-2010 875972109@GENIA Treebank@formal@@1@S@Our results demonstrate the regulation of STAT activity by a signaling pathway that regulates the T cell functional phenotype and is distinct from the cytokine-activated Janus kinase-STAT signaling pathway.@@@@1@30@@oe@16-12-2010 875973301@GENIA Treebank@formal@@1@S@Inhibition of T lymphocyte activation by cAMP is associated with down-regulation of two parallel mitogen-activated protein kinase pathways, the extracellular signal-related kinase and c-Jun N-terminal kinase.@@@@1@28@@oe@16-12-2010 875973302@GENIA Treebank@formal@@1@S@The induction of T cell proliferation requires signals from the TCR and a co-receptor molecule, such as CD28, that activate parallel and partially cross-reactive signaling pathways.@@@@1@29@@oe@16-12-2010 875973303@GENIA Treebank@formal@@1@S@These pathways are disrupted by agonists that utilize adenylate cyclase and cAMP-dependent protein kinase A (PKA).@@@@1@19@@oe@16-12-2010 875973304@GENIA Treebank@formal@@1@S@We found that the adenylate cyclase activator, forskolin, inhibits anti-CD3-induced shift in Lck electrophoretic mobility, suggesting an intervention at the TCR-coupled phosphoinositide turnover that precedes the activation of PKC.@@@@1@33@@oe@16-12-2010 875973305@GENIA Treebank@formal@@1@S@The shift of Lck following direct PKC activation by 12-O-tetradecanoyl phorbol 13-acetate, which bypasses early receptor-triggered biochemical events, is insensitive to forskolin.@@@@1@25@@oe@16-12-2010 875973306@GENIA Treebank@formal@@1@S@Nevertheless, forskolin also inhibits PKC downstream events, such as c-jun expression, which is critical for the activation process of T cells.@@@@1@25@@oe@16-12-2010 875973307@GENIA Treebank@formal@@1@S@To further analyze potential cross points between positively and negatively regulating signaling pathways in T cells, we tested the effects of activators of the adenylate cyclase or PKA on two parallel mitogen-activated protein kinase signaling pathways mediated by extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase.@@@@1@50@@oe@16-12-2010 875973308@GENIA Treebank@formal@@1@S@Using a PKC-specific inhibitor, GF109203X, or PKC-depleted T cells, we found that a large part of the anti-CD3-induced ERK activation is PKC dependent.@@@@1@27@@oe@16-12-2010 875973309@GENIA Treebank@formal@@1@S@Both PKC- dependent and -independent activation of ERK were sensitive to inhibition by forskolin or a cell-permeable cAMP analogue, dbcAMP.@@@@1@21@@oe@16-12-2010 875973310@GENIA Treebank@formal@@1@S@Furthermore, the effect of 12-O-tetradecanoyl phorbol 13-acetate and ionomycin, which synergized to fully activate c-Jun N-terminal kinase, was also sensitive to inhibition by forskolin.@@@@1@28@@oe@16-12-2010 875973311@GENIA Treebank@formal@@1@S@Our results suggest that PKA inhibits T cell activation by interfering with multiple events along the two signaling pathways operating downstream of the TCR and the CD28 co-receptor molecules.@@@@1@30@@oe@16-12-2010 876030901@GENIA Treebank@formal@@1@S@Abnormalities of p16, p15 and CDK4 genes in recurrent malignant astrocytomas.@@@@1@13@@oe@16-12-2010 876030902@GENIA Treebank@formal@@1@S@Abnormalities in the p16, p15 and CDK4 genes that regulate transition through the G1 phase of the cell cycle have been implicated in the malignant progression of astrocytomas.@@@@1@30@@oe@16-12-2010 876030903@GENIA Treebank@formal@@1@S@The results of the present study demonstrate that dysfunction of these genes also occurs during recurrence of glial tumors that were highly malignant at first presentation.@@@@1@27@@oe@16-12-2010 876030904@GENIA Treebank@formal@@1@S@Analysis of 10 matched pairs of high grade malignant astrocytomas and their subsequent recurrences identified three distinct groups.@@@@1@19@@oe@16-12-2010 876030905@GENIA Treebank@formal@@1@S@The primary and recurrent tumors in Group A did not show structural alterations in the p16, p15 or CDK4 genes, whereas homozygous codeletion of p16 and p15 was observed in both primary and recurrent tumors in Group B.@@@@1@41@@oe@16-12-2010 876030906@GENIA Treebank@formal@@1@S@The primary tumors in Group C had a normal profile of p16, p15 and CDK4 at presentation.@@@@1@19@@oe@16-12-2010 876030907@GENIA Treebank@formal@@1@S@Upon recurrence, however, the tumors sustained either deletion of p16 alone or codeletion of both p16 and p15 or amplification of CDK4.@@@@1@25@@oe@16-12-2010 876030908@GENIA Treebank@formal@@1@S@Analysis of the molecular differences between primary anaplastic astrocytomas/glioblastomas and their subsequent recurrences, which are clinically indistinguishable, may provide better therapeutic options for treatment.@@@@1@27@@oe@16-12-2010 876138101@GENIA Treebank@formal@@1@S@Transcriptional analysis of Epstein-Barr virus gene expression in EBV-positive gastric carcinoma: unique viral latency in the tumour cells.@@@@1@20@@oe@16-12-2010 876138102@GENIA Treebank@formal@@1@S@Although case-oriented evidence for an association of Epstein-Barr virus (EBV) with gastric carcinoma has been accumulating recently, the interaction(s) between EBV and gastric epithelial cells is/are largely unknown.@@@@1@35@@oe@16-12-2010 876138103@GENIA Treebank@formal@@1@S@In this study, we examined seven EBV-positive gastric carcinoma tissues for viral gene expression at the mRNA level, from which studies on the EBV oncogenicity in human epithelial cells will benefit.@@@@1@34@@oe@16-12-2010 876138104@GENIA Treebank@formal@@1@S@Reverse transcription-PCR analysis showed that all seven EBV-positive tumour tissues constitutively expressed EBV nuclear antigen (EBNA) 1 mRNA, but not EBNA2 mRNA.@@@@1@26@@oe@16-12-2010 876138105@GENIA Treebank@formal@@1@S@The EBNA transcription was initiated from one of three EBNA promoters, Qp: by contrast, both Cp and Wp were silent, thus resulting in the lack of EBNA2 mRNA.@@@@1@33@@oe@16-12-2010 876138106@GENIA Treebank@formal@@1@S@Latent membrane protein (LMP) 2A mRNA was detected in three of seven cases; however, neither LMP1 nor LMP2B mRNA was detected in any of the tumours tested.@@@@1@32@@oe@16-12-2010 876138107@GENIA Treebank@formal@@1@S@Transcripts from the BamHI-A region of the viral genome were detectable in all cases.@@@@1@15@@oe@16-12-2010 876138108@GENIA Treebank@formal@@1@S@BZLF1 mRNA and the product, an immediate-early gene for EBV replication, was not expressed in any of them, thereby suggesting that the tumour cells carried EBV genomes in a tightly latent form.@@@@1@36@@oe@16-12-2010 876138109@GENIA Treebank@formal@@1@S@These findings further extended our previous data regarding EBV latency in gastric carcinoma cells at the protein level, and have affirmed that the programme of viral gene expression in the tumour more closely resembles 'latency I' represented by Burkitt's lymphoma than 'latency II' represented by the majority of nasopharyngeal carcinomas.@@@@1@57@@oe@16-12-2010 876402701@GENIA Treebank@formal@@1@S@Chronic human immunodeficiency virus type 1 infection of myeloid cells disrupts the autoregulatory control of the NF-kappaB/Rel pathway via enhanced IkappaBalpha degradation.@@@@1@23@@oe@16-12-2010 876402702@GENIA Treebank@formal@@1@S@Productive human immunodeficiency virus type 1 (HIV-1) infection causes sustained NF-kappaB DNA-binding activity in chronically infected monocytic cells.@@@@1@21@@oe@16-12-2010 876402703@GENIA Treebank@formal@@1@S@A direct temporal correlation exists between HIV infection and the appearance of NF-kappaB DNA-binding activity in myelomonoblastic PLB-985 cells.@@@@1@20@@oe@16-12-2010 876402704@GENIA Treebank@formal@@1@S@To examine the molecular basis of constitutive NF-kappaB DNA-binding activity in HIV1 -infected cells, we analyzed the phosphorylation and turnover of IkappaBalpha protein, the activity of the double-stranded RNA-dependent protein kinase (PKR) and the intracellular levels of NF-kappaB subunits in the PLB-985 and U937 myeloid cell models.@@@@1@51@@oe@16-12-2010 876402705@GENIA Treebank@formal@@1@S@HIV-1 infection resulted in constitutive, low-level expression of type 1 interferon (IFN) at the mRNA level.@@@@1@20@@oe@16-12-2010 876402706@GENIA Treebank@formal@@1@S@Constitutive PKR activity was also detected in HIV-1-infected cells as a result of low-level IFN production, since the addition of anti-IFN-alpha/beta antibody to the cells decreased PKR expression.@@@@1@30@@oe@16-12-2010 876402707@GENIA Treebank@formal@@1@S@Furthermore, the analysis of IkappaBalpha turnover demonstrated an increased degradation of IkappaBalpha in HIV-1-infected cells that may account for the constitutive DNA binding activity.@@@@1@26@@oe@16-12-2010 876402708@GENIA Treebank@formal@@1@S@A dramatic increase in the intracellular levels of NF-kappaB subunits c-Rel and NF-kappaB2 p100 and a moderate increase in NF-kappaB2 p52 and RelA(p65) were detected in HIV-1-infected cells, whereas NF-kappaB1 p105/p50 levels were not altered relative to the levels in uninfected cells.@@@@1@44@@oe@16-12-2010 876402709@GENIA Treebank@formal@@1@S@We suggest that HIV-1 infection of myeloid cells induces IFN production and PKR activity, which in turn contribute to enhanced IkappaBalpha phosphorylation and subsequent degradation.@@@@1@27@@oe@16-12-2010 876402710@GENIA Treebank@formal@@1@S@Nuclear translocation of NF-kappaB subunits may ultimately increase the intracellular pool of NF-kappaB/IkappaBalpha by an autoregulatory mechanism.@@@@1@18@@oe@16-12-2010 876402711@GENIA Treebank@formal@@1@S@Enhanced turnover of IkappaBalpha and the accumulation of NF-kappaB/Rel proteins may contribute to the chronically activated state of HIV-1-infected cells.@@@@1@21@@oe@16-12-2010 876965001@GENIA Treebank@formal@@1@S@Sequence-specific DNA binding of the B-cell-specific coactivator OCA-B.@@@@1@9@@oe@16-12-2010 876965002@GENIA Treebank@formal@@1@S@B-cell-specific transcription of immunoglobulin genes is mediated by the interaction of a POU domain containing transcription factor Oct-1 or Oct-2, with the B-cell-specific coactivator OCA-B (Bob-1, OBF-1) and a prototype octamer element.@@@@1@37@@oe@16-12-2010 876965003@GENIA Treebank@formal@@1@S@We find that OCA-B binds DNA directly in the major groove between the two subdomains of the POU domain, requiring both an A at the fifth position of the octamer element and contact with the POU domain.@@@@1@39@@oe@16-12-2010 876965004@GENIA Treebank@formal@@1@S@An amino-terminal fragment of OCA-B binds the octamer site in the absence of a POU domain with the same sequence specificity.@@@@1@22@@oe@16-12-2010 876965005@GENIA Treebank@formal@@1@S@Coactivator OCA-B may undergo a POU-dependent conformational change that exposes its amino terminus, allowing it to recognize specific DNA sequences in the major groove within the binding site for Oct-1 or Oct-2.@@@@1@34@@oe@16-12-2010 876965006@GENIA Treebank@formal@@1@S@The recognition of both the POU domain and the octamer sequence by OCA-B provides a mechanism for differential regulation of octamer sites containing genes by the ubiquitous factor Oct-1.@@@@1@30@@oe@16-12-2010