Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is the product of the obese gene (ob), and is secreted in plasma from mature adipocytes. It has been recently reported that leptin is synthesized in granulosa and cumulus cells within the follicle of the ovary, and is present in mature human oocytes, suggesting possible roles of leptin in several aspects of pre- and post-ovulatory follicular development. On the other hand, STAT (Signal Transducer and Activator of Transcription) transcription factors are involved in leptin-associated signal transduction. In this report, we studied the expression of leptin receptor and STAT3 activation by leptin in metaphase 2 stage (M2) oocytes. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting showed that mRNA and protein of leptin receptor were expressed in M2 stage oocyte. Leptin at 15 ng/ml, the concentration observed in follicular fluid, caused tyrosine phosphorylation of STAT3 in mouse M2 stage oocytes. These results suggest possible roles of leptin in several aspects during oocyte maturation by activating the STAT signal transduction pathway.
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PMID:Tyrosine phosphorylation of STAT3 by leptin through leptin receptor in mouse metaphase 2 stage oocyte. 1008 Sep 23

Interleukin-10 (IL-10) has been used in the treatment of viral hepatitis in interferon-alpha (IFN-alpha) non-responders while patients who have high levels of IL-10 are poorly responsive to IFN-alpha. The mechanism underlying such controversial functions of IL-10 remains unknown. Here we demonstrated that injection of IL-10 into mice attenuated IFN-alpha-induced signal transducer and activator transcription factor (STAT)1 tyrosine phosphorylation in the liver. Reverse transcriptase-polymerase chain reaction assay demonstrated that mouse liver expressed high levels of IL-10 receptor 2 (IL-10R2) but low levels of IL-10R1. Injection of IL-10 into mice activated STAT3 but not STAT1 tyrosine phosphorylation and induced suppressor of cytokine signal 2 (SOCS2), SOCS3, and cytokine-inducible SH2 protein (CIS) mRNA expression in the liver. Furthermore, overexpression of SOCS2 or SOCS3 inhibited IFN-alpha-induced reporter activity in hepatic cells. These findings suggest that IL-10 inhibits IFN-alpha-activated STAT1 in the liver, at least in part, by inducing SOCS2, SOCS3, and CIS expression, which may be responsible for the resistance of IFN-alpha therapy in patients who have high levels of IL-10 and recommends that IL-10 treatment for viral hepatitis should be cautious.
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PMID:IL-10 attenuates IFN-alpha-activated STAT1 in the liver: involvement of SOCS2 and SOCS3. 1103 14

Previous work in this laboratory has shown an increase of both mRNA and protein for suppressor of cytokine signaling 3 (SOCS3) in rat liver after thermal injury. This study identifies which liver cell type (parenchymal or non-parenchymal) is responsible for the postburn increase in SOCS3 and how this increase is connected to the signal transducer and activator of transcription (STAT) pathway. Parenchymal (hepatocytes) and non-parenchymal cells were isolated by Liberase digestion from postburn day 1 (PBD1) rats (including sham controls) and were analyzed for the expression of SOCS3 mRNA and protein and STAT3 and p-STAT3 protein. Reverse transcriptase (RT)-PCR performed on the isolated cells showed a significant increase of SOCS3 in the hepatocytes, but not in the non-parenchymal cells. When isolated hepatocytes from rats and the human hepatocyte cell line, HepG2, were cultured in the presence of IL-6, both showed an increase in SOCS3 mRNA expression. Anti-SOCS3, anti-STAT3, and anti-phosphorylated STAT3 labeling in both postburn rat liver and isolated hepatocyte cells that were cultured in the presence of IL-6 revealed that an increase in SOCS3 protein was accompanied by decrease in STAT3 protein. We propose that thermal injury stimulates non-parenchymal cells to produce cytokines, including IL-6, which in tum stimulate the Jak/STAT pathway in hepatocytes. The signal transduction pathway triggered by non-parenchymal cells causes an increase in SOCS3 production, which in turn induces the reduction of STAT3 protein in the hepatocytes.
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PMID:Thermal injury-induced increases of hepatocyte SOCS3 lead to decreases in STAT3. 1239 83

Activated forms of STAT3 transcription factors are often found in various cancers and tumor cell lines, indicating that this signaling pathway is involved in tumorogenesis. At the molecular level, STAT3 proteins function as transcriptional activators and up-regulate several growth-promoting genes such as myc, pim-1, or cyclin D1. However, these transcription factors have also proapoptotic functions and can activate the expression of the cell-cycle inhibitor p21(waf1), suggesting that STAT3 can also block cell-cycle progression and prevent abnormal cell proliferation. To reconcile these observations, one would predict that the STAT3-mediated activation of p21(waf1) is lost during cell transformation. In this study, we show that upon IL-6 stimulation of glioblastoma cells, STAT3 does not activate the expression of the p21(waf1) gene, whereas the expression of the myc gene remains unaltered. Chromatin immunoprecipitation experiments show that STAT3 and its cofactor NcoA/SRC1a are effectively recruited to the p21(waf1) promoter but that this is not followed by the association of the CREB-binding protein (CBP) histone acetylase and the type II RNA polymerase as normally seen on the myc promoter. Whereas the PI-3K/Akt pathway is constitutively activated in these cells, inactivation of this pathway restores the loading of CBP and the RNA polymerase and the expression of the p21(waf1) gene without having any effect on myc regulation. Moreover, this effect was recapitulated in HepG2 cells expressing an activated form of the Akt kinase. In these cells, the kinase blocked the STAT3-mediated expression of the p21(waf1) gene by inhibiting the recruitment of CREB-binding protein and the type II RNA polymerase, without having any effects on the loading of STAT3 and its cofactor NcoA/SRC1a. Together, these findings suggest that the phosphatidylinositol 3-kinase/Akt pathway inhibits the transcriptional activation of the p21(waf1) gene by STAT3 proteins without altering the regulation of the myc promoter.
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PMID:Opposite regulation of myc and p21waf1 transcription by STAT3 proteins. 2492 63

We describe a detailed time course of the assembly and disassembly of a STAT3-dependent, glucocorticoid-supplemented enhanceosome for the alpha2-macroglobulin (alpha2-M) gene and compare this with a detailed time course of transcription of the gene by run-on analysis. The glucocorticoid receptor (GR) can associate with the enhanceosome without STAT3. Furthermore, the enhanceosome contains c-Jun/c-Fos and OCT-1 constitutively. All of these factors (GR, c-Jun, OCT-1) have transcription activation domains, but STAT3 is required for the observed transcriptional increase. The time course of enhanceosome occupation by GR and tyrosine-phosphorylated STAT3 shows that these transcription factors precede by approximately 5-10 min the arrival of RNA polymerase II (Pol II). The enhanceosome remains assembled for approximately 90 min in the continued presence of both inducers. When IL-6 and Dex are removed (after 30 min of treatment), the disappearance within an additional 30 min of the established enhanceosome indicates that renewal of STAT3 and GR binding must occur in the continued presence of IL-6+Dex. Compared with the total nuclear tyrosine-phosphorylated STAT3 capable of binding DNA, the chromatin-associated STAT3 resists dephosphorylation and appears to recycle to maintain the enhanceosome. Run-on transcription shows a lag after full enhanceosome occupation that can be largely but not completely explained by the approximately 30 min transit time of Pol II across the alpha2-Mlocus.
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PMID:STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene. 1452 52

STAT transcription factors (signal transducers and activators of transcription) are cytoplasmic proteins that induce gene activation in response to cytokine receptor stimulation. Following tyrosine phosphorylation, STAT proteins translocate into the nucleus and activate specific target genes. We have previously reported that STAT3 activates the expression of the p21waf1 gene through its association with the NcoA/SRC1a and CBP coactivators. In this study, we explore the role of BRG1, a component of the SWI/SNF chromatin-remodeling complex, and the role of cdk9, a component of the elongation factor P-TEFb, in the STAT3-mediated expression of p21waf1. We found using pull-down experiments and co-immunoprecipitation assays that both proteins associate with STAT3. Chromatin immunoprecipitation (ChIP) experiments indicate that STAT3 DNA binding results in histone H3 acetylation and BRG1 recruitment. Using Southern blot analysis, we found that the loading of BRG1 is followed by an increased accessibility of the proximal p21waf1 promoter and by the association of RNA polymerase II. As a next step, STAT3 then recruits the cdk9 kinase to phosphorylate the carboxy-terminal domain of the RNA polymerase at serine 2. Accordingly, the elongating form of the polymerase can be detected by ChIP experiments on the coding region of the gene, probably initiating mRNA synthesis. Therefore, STAT3 not only promotes the initiation of transcription but also regulates chromatin remodeling and transcription elongation through its interaction with BRG1 and cdk9.
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PMID:Implication of BRG1 and cdk9 in the STAT3-mediated activation of the p21waf1 gene. 1528 5

STAT3 regulates many target genes in response to cytokines and growth factors. To study the mechanisms of STAT3-dependent transcription, we established several cell lines in which HepG2-STAT3-knockdown cells were reconstituted with a variety of STAT3 mutants. Using these cell lines, we found that truncated STAT3(1-750), but not STAT3(1-761), could not recruit SRC-1/NcoA-1 and was not phosphorylated on Ser727. Furthermore, mutation of STAT3 L755 and F757 to alanines caused the loss of STAT3-dependent SRC-1 recruitment, leaving Ser727 phosphorylation intact. Consistent with this, the STAT3-L755A/F757A mutant showed no increase in acetylated histone H3 at Lys14 and a decreased level of RNA polymerase II recruited to the target gene promoter, although p300 recruitment and histone H4 acetylation were intact. This mutant also lost responsiveness to co-expressed SRC-1. Thus, the conserved STAT3 region from 752 to 761, called STAT3 CR2, plays critical roles in STAT3-dependent transcription by recruiting SRC-1 and allowing Ser727 phosphorylation.
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PMID:Region 752-761 of STAT3 is critical for SRC-1 recruitment and Ser727 phosphorylation. 1553 Apr 26

Besides its function as a cell cycle regulator, cyclin D1 interacts with transcription factors to regulate gene activation. In this study, we show that cyclin D1 is recruited to the p21waf1 promoter by a STAT3-NcoA complex. The association of cyclin D1 with DNA prevented the recruitment of the CBP histone acetylase and RNA polymerase II, leading to an inhibition of the p21waf1 gene. Confirming the transcriptional function of the protein, the expression of the p21waf1 gene was enhanced in cyclin D1-/- fibroblasts or upon siRNA-mediated down-regulation of the cyclin. Moreover, the STAT3-mediated activation of p21waf1 was also inhibited in breast cancer cells containing elevated levels of cyclin D1. Altogether, these results suggest that the transcriptional activities of cyclin D1 might play an important role in the regulation of cell-cycle regulatory genes and that these functions are probably involved in cell transformation.
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PMID:Transcriptional regulation by a DNA-associated form of cyclin D1. 1565 54

The STAT3 (signal transducer and activator of transcription) transcription factor functions as down-stream effector of growth factor signaling. Whereas STAT3 activation is transient in normal cells, constitutively activated forms of the transcription factor have been detected in several cancer cell lines and primary tumors. Through the up-regulation of cell cycle and survival genes, STAT3 plays important roles in cell growth, anti-apoptosis, and cell transformation yet the molecular basis for this behavior is poorly understood. In this study, we show that STAT3 and its transcriptional cofactors are recruited to the promoter of the Cdc25A gene to activate its expression. Using chromatin immunoprecipitations, we observed that Myc is recruited to this promoter following STAT3 DNA binding. Moreover, small interfering RNA-mediated knockdown of Myc specifically inhibits the STAT3-mediated activation of Cdc25A. Reduction in Myc protein level results in defective recruitment of the CREB-binding protein, Cdk9, and RNA polymerase complexes, indicating that Myc is necessary for STAT3 transcription. Surprisingly, the association of STAT3 with the Cdc25A promoter does not necessarily lead to transcriptional induction because this protein also functions as a transcriptional repressor of the Cdc25A gene. Following hydrogen peroxide stimulation, STAT3 forms a repressor complex with the retinoblastoma (Rb) tumor suppressor to occupy the Cdc25A promoter and block its induction. In coimmunoprecipitations and ChIP experiments, Rb was found to associate with STAT3 on DNA and we provide evidence that Rb binds directly to the transcription factor. Thus, we propose that Myc and STAT3 cooperate to induce the expression of Cdc25A and that their transcriptional activity is normally regulated by the Rb tumor suppressor gene.
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PMID:The STAT3 transcription factor is a target for the Myc and riboblastoma proteins on the Cdc25A promoter. 1567 71

PAF, which is composed of Paf1, Cdc73, Ctr9, Leo1, and Rtf1, is a novel complex with multiple functions in transcription-related activities. The PAF complex interacts with histone-modifying enzymes and RNA polymerase II to regulate transcription. With general transcription regulatory potential in yeast, Hyrax/Cdc73 has been reported to associate with beta-catenin to control Wnt/Wg signal-specific transcription in Drosophila. Here, we present the first evidence of IL-6 signal-specific transcriptional regulation by SH2BP1/CTR9 in mammals. Upon LPS injection of mice, we observed transient induction of the mammalian PAF complex in the liver. Inhibition of CTR9 specifically abrogated expression of IL-6-responsive genes, but had no effect on genes constitutively expressed or induced by interferon-beta, TNFalpha, or IL-1beta. The PAF complex was found in the promoter regions of IL-6-responsive HP and FGGgamma, but not in the promoter region of constitutively active GAPDH. Transcriptional activation by STAT3 was inhibited when CTR9 siRNA was introduced, whereas transcriptional activation was enhanced by mCtr9 overexpression. IL-6-activated Stat3 was found to co-localize and interact with CTR9. In CTR9-depleted cells, decreased STAT3 association with the promoter regions, as well as impaired K4-trimethylation of histone H3 in the coding regions, of target genes was observed. These data suggest that CTR9 participates in the transcription of IL-6-responsive genes through the regulation of DNA association of STAT3 and modification of histone methylation.
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PMID:hCTR9, a component of Paf1 complex, participates in the transcription of interleukin 6-responsive genes through regulation of STAT3-DNA interactions. 1791 Nov 13


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