Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.3.23 (GAS)
 957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence to suggest that obese populations have an increased susceptibility to various pathologic disorders. Both AP-1 and STAT nuclear binding proteins have been suggested to play a role in certain obesity-related diseases. The objective of our studies reported herein was to compare constitutive binding activity of nuclear proteins (AP-1, GR, and STAT), that may be relevant to obesity-related diseases in the obese (fa/fa) Zucker rat to lean (Fa/?) littermates. AP-1, GR, and STAT liver nuclear protein binding activity was analyzed using the electrophoretic mobility shift assay (EMSA). EMSA analysis of liver nuclear protein from obese and lean Zucker rats revealed high constitutive AP-1 binding activity in the obese animals. AP-1 binding activity in the obese rats was not further elevated by treatment with phenobarbital, a known inducer of AP-1 binding activity. No differences were observed in GR binding to a consensus GRE between obese and lean animals; however, STAT binding activity to a consensus GAS element was lower in liver tissue from obese Zucker rats. Our findings presented herein suggest that the fa/fa Zucker rat may be a suitable obese rodent model for studying the roles AP-1 and STAT may play in the pathologies of these diseases.
 ...
PMID:Characterization of nuclear protein binding (AP-1, GR, and STAT) in the genetically obese (fa/fa) Zucker rat. 976 71

HC class I expression can be up-regulated by interferons (IFN) and other cytokines. Both IFNalpha and IFNgamma have been shown to exert their effects via a recently discovered signalling pathway by inducing tyrosine phosphorylation of their receptors. Receptors for interferons and other cytokines signal through the action of associated protein tyrosine kinases of the JAK family (Janus kinase) and latent cytoplasmic transcriptional activators from the STAT family (signal transducers and activators of transcription). Here we report a gastric adenocarcinoma cell line, AGS, that is defective in its response to either IFNalpha or IFNgamma. AGS cells display selective alterations only in MHC class I inducibility and not in constitutive MHC class I expression. In nuclear extracts of AGS cells, no binding activity to interferon-responsive elements (GAS/ISRE) was observed. We found that AGS cells showed an extremely low level of STAT1 expression, which may be responsible for the absence of biological response to IFN. Because STAT1-deficient cells are highly sensitive to infection by virus, the absence of these proteins may also contribute to the tumor phenotype, giving the tumor a selective advantage, by inhibiting cell growth suppression mediated by IFN and abetting escape from the T cell antitumor response.
 ...
PMID:Unresponsiveness to interferon associated with STAT1 protein deficiency in a gastric adenocarcinoma cell line. 976 20

Cytokines and steroid hormones use different sets of signal transduction pathways, which seem to be unrelated. Interleukin-6 (IL-6) uses JAK tyrosine kinase and STAT (signal transducer and activator of transcription) transcription factor. Glucocorticoid binds glucocorticoid receptor (GR), which is a member of the steroid receptor superfamily. We have studied the crosstalk between the IL-6-JAK-STAT and glucocorticoid-nuclear receptor pathways. IL-6 and glucocorticoid synergistically activated the IL-6 response element on the rat alpha2-macroglobulin promoter (APRE)-driven luciferase gene. The exogenous expression of GR enhanced the synergism. The exogenous expression of dominant negative STAT3 completely abolished the IL-6 plus glucocorticoid-induced activation of the APRE-luciferase gene. Tyrosine phosphorylation of STAT3 stimulated by IL-6 alone was not different from that by IL-6 plus glucocorticoid. The protein level of STAT3 was also not increased by glucocorticoid stimulation. The time course of STAT3 tyrosine phosphorylation by IL-6 plus glucocorticoid was not different from that by IL-6 alone. The synergism was studied on the two other IL-6 response elements, the junB promoter (JRE-IL-6) and the interferon regulatory factor-1 (IRF-1) promoter (IRF-GAS) which could be activated by STAT3. The synergistic activation by glucocorticoid on the IL-6-activated JRE-IL-6 and the IRF-GAS-driven luciferase gene was not detected. Glucocorticoid did not change the mobility of IL-6-induced APRE-binding proteins in a gel shift assay. These results suggest that the synergism was through the GR and STAT3, and the coactivation pathway which was specific for APRE was the target of glucocorticoid.
 ...
PMID:Crosstalk between the interleukin-6 (IL-6)-JAK-STAT and the glucocorticoid-nuclear receptor pathway: synergistic activation of IL-6 response element by IL-6 and glucocorticoid. 979 74

Interferon-alpha (IFN-alpha) is a pleiotropic cytokine that has antiviral, antiproliferative, and immunoregulatory functions. There is increasing evidence that IFN-alpha has an important role in T-cell biology. We have analyzed the expression of IL-2Ralpha, c-myc, and pim-1 genes in anti-CD3-activated human T lymphocytes. The induction of these genes is associated with interleukin-2 (IL-2)-induced T-cell proliferation. Treatment of T lymphocytes with IFN-alpha, IL-2, IL-12, and IL-15 upregulated IL-2Ralpha, c-myc, and pim-1 gene expression. IFN-alpha also sensitized T cells to IL-2-induced proliferation, further suggesting that IFN-alpha may be involved in the regulation of T-cell mitogenesis. When we analyzed the nature of STAT proteins capable of binding to IL-2Ralpha, pim-1, and IRF-1 GAS elements after cytokine stimulation, we observed IFN-alpha-induced binding of STAT1, STAT3, and STAT4, but not STAT5 to all of these elements. Yet, IFN-alpha was able to activate binding of STAT5 to the high-affinity IFP53 GAS site. IFN-alpha enhanced tyrosine phosphorylation of STAT1, STAT3, STAT4, STAT5a, and STAT5b. IL-12 induced STAT4 and IL-2 and IL-15 induced STAT5 binding to the GAS elements. Taken together, our results suggest that IFN-alpha, IL-2, IL-12, and IL-15 have overlapping activities on human T cells. These findings thus emphasize the importance of IFN-alpha as a T-cell regulatory cytokine.
 ...
PMID:Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. 1006 71

It has been demonstrated that interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) have various reverse effects on macrophages; however, the molecular mechanism of this difference has not been fully understood. In this study, we analyzed the binding activity of IL-10- and IFN-gamma-activated STAT molecules to two kinds of GAS-motif sequences. IL-10-activated STAT1 could bind to the GAS-motif sequence in the promoter region of the Fcgamma receptor, but not to that in the promoter region of the COX-2 gene, whereas IFN-gamma-activated STAT1 and STAT5 could bind to both sequences. IL-10 inhibited IFN-gamma-induced STAT activation without newly synthesized protein. We further demonstrated that aspirin, but not dexamethasone, suppressed IFN-gamma-induced STAT activation. Taken together, these results suggest that IL-10-activated STAT1 has a specificity in binding to the GAS-motif sequences, whereas IFN-gamma-activated STAT1 and STAT5 have a broader spectrum in binding to the GAS-motif sequences. This may explain the difference between IL-10 and IFN-gamma in biological activity, and the inhibitory effect of IL-10 on IFN-gamma activities.
 ...
PMID:Selective DNA-binding activity of interleukin-10-stimulated STAT molecules in human monocytes. 1043 70

Interferons (IFNs) encode a large family of multifonctional secreted proteins that are involved in antiviral defense, the regulation of cell growth and modulation of the immune response. They are subdivided into two types that activate transduction pathways via different cell surface receptors. Binding of both IFN type I and II results in the differential activation of JAK (Janus kinases) that phosphorylate latent cytoplasmic transcription factors termed STATs (signal transducer and activator of transcription). Phosphorylated STATs translocate to the nucleus, bind specific DNA elements and direct transcription. Type I IFN induces the phosphorylation of STAT1 and STAT2 proteins by tyrosine phosphorylation involving the type I IFN receptor-associated tyrosine kinases TYK2 and JAK1. Following phosphorylation, STAT1 and STAT2 form the transcriptionally active IFN-stimulated gene factor 3 (ISGF3) by association with a protein of the IFN regulatory factor (IRF) family, p48. The specificity of the transcriptional activation by ISGF3 is mediated by specific elements termed IFN-stimulatory response element (ISRE) located in the promoter region of IFN-inducible genes. ISREs drive the expression of most IFN type I-regulated genes and a few IFN type II-regulated genes. Gene induction by type II IFN involves the phosphorylation of only STAT1 by JAK1 and Jak2 kinases. This phosphorylation generates a homodimer of STAT1 which is able to bind the IFNgamma-activated site (GAS) to activate transcription. This signaling is rapid and direct. Molecules involved in the IFN signaling pathways have been shown to be used by other polypeptide ligands in their own signal transduction pathways. Pathways other than JAK/STAT are also involved in IFN signaling, but their mechanisms are less clear. The best documented are the mitogen-activated protein kinase (MAPK) cascade, the components of the TCR (T cell receptor) signaling cascade and the Pi3 kinase pathway.
 ...
PMID:[Interferon signaling pathways]. 1058 7

The activation status of a recently identified STAT (signal transducers and activators of transcription) factor, LIL-Stat (lipopolysaccharide [LPS]/IL-1-inducible Stat) in adult T-cell leukemia (ATL) cells was investigated by electrophoretic mobility shift assays using nuclear extracts of leukemic cells from 7 patients with ATL and a GAS (gamma interferon activation site)-like element termed LILRE (LPS/IL-1-responsive element), which is found in the human prointerleukin 1beta (IL1B) gene. Spontaneous DNA binding of LIL-Stat was observed in all ATL cells examined. However, in normal human peripheral lymphocytes, DNA binding of LIL-Stat was detected only after stimulation with IL-1. These results demonstrated that LIL-Stat is constitutively activated in ATL cells. Furthermore, our transient transfection studies using LILRE chloramphenicol acetyltransferase (CAT) reporters argue that LIL-Stat in ATL cells functions as a transcriptional activator through binding to the LILRE in the IL1B gene. (Blood. 2000;95:2715-2718)
 ...
PMID:Constitutive activation of LIL-Stat in adult T-cell leukemia cells. 1075 55

TSH is known as an important hormone that plays the major role not only in the maintenance of normal physiology but also in the regulation of immunomodulatory gene expression in thyrocytes. The adhesion molecule intercellular adhesion molecule-1 (ICAM-1) was identified as one of the proteins that are abnormally expressed in the thyroid gland during autoimmune thyroid diseases. In this study we found that TSH inhibits interferon-gamma (IFNgamma)-mediated expression of the ICAM-1 gene, and we investigated the involved mechanisms in rat FRTL-5 thyroid cells. After exposure to IFNgamma, ICAM-1 expression is positively regulated at the level of transcription. This effect occurs via the IFNgamma-activated site (GAS) element in the ICAM-1 promoter as a consequence of the activation of STAT1 (signal transducer and activator of transcription-1), but not of STAT3. On the other hand, after exposure to TSH plus IFNgamma, ICAM-1 transcription is negatively modulated. We found that this inhibitory effect of TSH also occurs via the GAS element. Electrophoretic mobility shift assays confirmed that the IFNgamma-induced DNA-binding activities of STAT1 were reduced by TSH. Furthermore, our results showed that the inhibitory effect of TSH on IFNgamma signaling is caused by inhibition of tyrosine phosphorylation on STAT1, Janus kinase-1 (Jak1), and IFNgamma receptor a, but not Jak2. In conclusion, we have identified a novel mechanism in which TSH modulates the IFNgamma-mediated Jak/STAT signaling pathway through the inhibition of Jak1 and STAT1.
 ...
PMID:Thyrotropin modulates interferon-gamma-mediated intercellular adhesion molecule-1 gene expression by inhibiting Janus kinase-1 and signal transducer and activator of transcription-1 activation in thyroid cells. 1083 Feb 95

STAT6 mediates interleukin-4 (IL-4)-dependent positive and negative regulation of inflammatory gene expression. In the present report we examined the molecular mechanisms involved in IL-4-induced repression of reporter gene transcription driven by STAT1 and/or NF-kappaB. Transient expression of STAT6 in a STAT6-deficient cell line (HEK 293) conferred sensitivity to IL-4 for STAT6-dependent transcription and for repression of interferon-gamma (IFNgamma)/STAT1- and/or tumor necrosis factor-alpha (TNFalpha)/NF-kappaB-driven reporter gene expression. In cells transfected with a deletion mutant of STAT6 lacking its transactivating domain, IL-4 could not mediate either positive or negative control of reporter gene expression. Overexpression of CREB-binding protein dramatically enhanced IL-4/STAT6-stimulated transcription and overcame IL-4-mediated repression of TNFalpha/NF-kappaB-dependent but not IFNgamma/STAT1-dependent transcription. A single amino acid change in the DNA-binding domain of STAT6 (H415A) selectively reduced the affinity of STAT6 for IL-4-responsive STAT sequence motifs (N4) without affecting the affinity for IFNgamma-responsive (GAS) sequences (N3) and, accordingly, eliminated transcription from an IL-4-responsive promoter. Interestingly, this mutation eliminated IL-4-mediated suppression of reporter gene transcription stimulated by TNFalpha/NF-kappaB but retained nearly full capacity to suppress IFNgamma/STAT1-stimulated transcription. Taken together these results demonstrate that STAT6 mediates suppression of STAT1 and NF-kappaB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site (i.e. N3 versus N4).
 ...
PMID:Interleukin-4/STAT6 represses STAT1 and NF-kappa B-dependent transcription through distinct mechanisms. 1098 6

It is well established that engagement of the Type I interferon (IFN) receptor results in activation of JAKs (Janus kinases), which in turn regulate tyrosine phosphorylation of STAT proteins. Subsequently, the IFN-dependent tyrosine-phosphorylated/activated STATs translocate to the nucleus to regulate gene transcription. In addition to tyrosine phosphorylation, phosphorylation of Stat1 on serine 727 is essential for induction of its transcriptional activity, but the IFNalpha-dependent serine kinase that regulates such phosphorylation remains unknown. In the present study we provide evidence that PKC-delta, a member of the protein kinase C family of proteins, is activated during engagement of the Type I IFN receptor and associates with Stat1. Such an activation of PKC-delta appears to be critical for phosphorylation of Stat1 on serine 727, as inhibition of PKC-delta activation diminishes the IFNalpha- or IFNbeta-dependent serine phosphorylation of Stat1. In addition, treatment of cells with the PKC-delta inhibitor rottlerin or the expression of a dominant-negative PKC-delta mutant results in inhibition of IFNalpha- and IFNbeta-dependent gene transcription via ISRE or GAS elements. Interestingly, PKC-delta inhibition also blocks activation of the p38 MAP kinase, the function of which is required for IFNalpha-dependent transcriptional regulation, suggesting a dual mechanism by which this kinase participates in the generation of IFNalpha responses. Altogether, these findings indicate that PKC-delta functions as a serine kinase for Stat1 and an upstream regulator of the p38 MAP kinase and plays an important role in the induction of Type I IFN-biological responses.
 ...
PMID:Protein kinase C-delta (PKC-delta ) is activated by type I interferons and mediates phosphorylation of Stat1 on serine 727. 1183 38


<< Previous 1 2 3 4 5 Next >>