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)

To try to elucidate the relationship between the radiosensitivity of NPC cell lines and ATM gene, this study was designed to investigate the mutation of ATM/PI3K region in NPC cell lines with different radiosensitivity. Two NPC cell lines of CNE1 and CNE2 with different radiosensitivities were established. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to get a 546bp fragment (8578nt-9123nt) of ATM cDNA, containing the PI-3 kinase domain (8753-8815bp). Direct sequencing of RT-PCR product was applied to determine the mutations in the gene. The sequence of the 546bp fragment is identical to the sequence of ATM gene published in GenBank, that is, there are no any mutations on the fragment of ATM/PI3K we examined either in CNE1 or in CNE2. It indicates that there may be no correlations between the mutation of ATM/PI3K and the variation of radiosensitivity in NPC cell lines CNE1, CNE2.
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PMID:[Study on mutation of ATM/PI3K region in NPC cell lines with different radiosensitivity]. 1563 69

The PI3K/Akt pathway plays a critical role in the regulation of gene expression induced by numerous stimuli. p300, a transcriptional coactivator, acts in concert with transcription factors to facilitate gene expression. Here, we show that Akt is activated and translocated to the nucleus in response to tumor necrosis factor alpha. Nuclear Akt associates with p300 and phosphorylates its Ser-1834 both in vivo and in vitro. The phosphorylation induces recruitment of p300 to the ICAM-1 promoter, leading to the acetylation of histones in chromatin and association with the basal transcriptional machinery RNA polymerase II. These two events facilitate ICAM-1 gene expression and are abolished by the p300 S1834A mutant, inhibitors of PI3K/Akt, or small interfering RNA of Akt. Histone acetylation is attributed to the Akt-enhanced intrinsic histone acetyltransferase (HAT) activity of p300 and its association with another HAT, p/CAF. Our study provides a new insight into the molecular mechanism by which Akt promotes the transcriptional potential of p300.
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PMID:Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity. 1602 95

We have previously demonstrated that the transcription factor NF-kappaB is activated by histone deacetylase inhibitors in a PI3K/Akt-dependent manner. The molecular mechanisms governing this process have not been well described. By virtue of their inhibitory action, it is unclear whether the addition of histone deacetylase inhibitors simply preserves the acetylation status of RelA/p65 or whether they actively stimulate signaling cascades that result in increased acetylation and transcription of NF-kappaB. Here we provide evidence that suberoylanilide hydroxamic acid stimulates NF-kappaB transcription through a signaling cascade that involves activation of both the serine/threonine kinase Akt and the p300 acetyltransferase. Using newly developed phosphospecific antibodies to p300 (pSer(1834)), and site-directed mutant proteins, we find that suberoylanilide hydroxamic acid stimulates Akt activity, which is required to phosphorylate p300 at Ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity as measured by an increased acetylation of RelA/p65 at Lys(310), a modification that is required for full NF-kappaB transcription. Importantly, coordinate activation of Akt/p300 pathway by suberoylanilide hydroxamic acid occurs at the chromatin level, resulting in recruitment of activated Akt (pSer(473)), p300 (pSer(1834)), acetylated RelA/p65 (Lys(310)), and RNA polymerase II to the NF-kappaB-dependent cIAP-2 and Bfl-1/A1 promoters. These studies provide evidence that histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid, not only inhibit deacetylase activity but also stimulate active NF-kappaB transcription and cell survival through signaling pathways involving Akt and increased p300 acetyltransferase activity.
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PMID:Suberoylanilide hydroxamic acid induces Akt-mediated phosphorylation of p300, which promotes acetylation and transcriptional activation of RelA/p65. 1692 51

The current investigation evaluates the expression of phosphatidylinositol kinase (PIK) genes in the parasitic protozoan, Giardia lamblia. The G. lamblia Genome Database revealed the presence of two putative phosphatidylinositol-3-kinase (gPI3K) and one phosphatidylinositol-4-kinase (gPI4K) genes resembling the catalytic subunit of eukaryotic PIKs. Primers, designed to amplify mRNA of these three genes, were used to measure transcription by quantitative reverse-transcriptase polymerase chain reactions. Results suggest that all three PIK genes are expressed in non-encysting and encysting trophozoites. The relative levels of the mRNA were highest in parasites cultured in pre-encysting medium that contained no bile. Two inhibitors of PI3K, LY 294002 and wortmannin were found to inhibit the growth of the trophozoite in culture. However, wortmannin was more effective than LY294002. Altogether, the present study indicates that Giardia is capable of expressing PIKs that are necessary for the growth and differentiation of this pathogen.
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PMID:Transcriptional analysis of three major putative phosphatidylinositol kinase genes in a parasitic protozoan, Giardia lamblia. 1730 May 15

Apigenin, a dietary plant-flavonoid has shown anti-proliferative and anticancer properties, however the molecular basis of this effect remains to be elucidated. We studied the molecular events of apigenin action in human prostate cancer cells. Treatment of LNCaP and PC-3 cells with apigenin causes G0-G1 phase arrest, decrease in total Rb protein and its phosphorylation at Ser780 and Ser807/811 in dose- and time-dependent fashion. Apigenin treatment caused increased phosphorylation of ERK1/2 and JNK1/2 and this sustained activation resulted in decreased ELK-1 phosphorylation and c-FOS expression thereby inhibiting cell survival. Use of kinase inhibitors induced ERK1/2 phosphorylation, albeit at different levels, and did not contribute to cell cycle arrest in comparison to apigenin treatment. Despite activation of MAPK pathway, apigenin caused a significant decrease in cyclin D1 expression that occurred simultaneously with the loss of Rb phosphorylation and inhibition of cell cycle progression. The reduced expression of cyclin D1 protein correlated with decrease in expression and phosphorylation of p38 and PI3K-Akt, which are regulators of cyclin D1 protein. Interestingly, apigenin caused a marked reduction in cyclin D1, D2 and E and their regulatory partners CDK 2, 4 and 6, operative in G0-G1 phase of the cell cycle. This was accompanied by a loss of RNA polymerase II phosphorylation, suggesting the effectiveness of apigenin in inhibiting transcription of these proteins. This study provides an insight into the molecular mechanism of apigenin in modulating various tyrosine kinases and perturbs cell cycle progression, suggesting its future development and use as anticancer agent in humans.
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PMID:Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells. 1745 54

The gene of mouse kappa opioid receptor (KOR) utilizes two promoters, P1 and P2. P1 is active in various brain areas and constitutively in P19 mouse embryonal carcinoma cells. P2 is active in limited brain stem areas of adult animals and only in late differentiated cells of P19 induced for neuronal differentiation in the presence of nerve growth factor (NGF). NGF response of P2 was found to be mediated by a specific binding site for transcription factor activation protein 2 (AP2) located in P2. Electrophoretic gel shift assay showed specific binding of this AP2 site by AP2beta, but not AP2alpha. Knockdown of endogenous AP2beta with siRNA abolished the stimulating effect of NGF on the expression of transcripts driven by P2. Binding of endogenous AP2beta on the endogenous KOR P2 chromatin region was also confirmed by chromatin immunoprecipitation. The effect of NGF was inhibited by LY2942002 (phosphatidylinositol 3-kinase, PI3K inhibitor), suggesting that PI3K was involved in signaling pathway mediating the effect of NGF stimulation on KOR P2. The chromatin of P2 in P19 was found to be specifically modified following NGF stimulation, which included demethylation at Lys9 and dimethylation at Lys4 of histone H3 and was consistent with the increased recruitment of RNA polymerase II to this promoter. This study presents the first evidence for epigenetic changes occurred on a specific KOR promoter triggered by NGF in cells undergoing neuronal differentiation. This epigenetic change is mediated by recruited AP2beta to this promoter and involves the PI3K system.
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PMID:Epigenetic regulation of kappa opioid receptor gene in neuronal differentiation. 1820 39

After interaction with its receptor, GM-CSF induces phosphorylation of the beta-chain in two distinct domains in macrophages. One induces activation of mitogen-activated protein kinases and the PI3K/Akt pathway, and the other induces JAK2-STAT5. In this study we describe how trichostatin A (TSA), which inhibits deacetylase activity, blocks JAK2-STAT5-dependent gene expression but not the expression of genes that depend on the signal transduction induced by the other domain of the receptor. TSA treatment inhibited the GM-CSF-dependent proliferation of macrophages by interfering with c-myc and cyclin D1 expression. However, M-CSF-dependent proliferation, which requires ERK1/2, was unaffected. Protection from apoptosis, which involves Akt phosphorylation and p21(waf-1) expression, was not modified by TSA. GM-CSF-dependent expression of MHC class II molecules was inhibited because CIITA was not induced. The generation of dendritic cells was also impaired by TSA treatment because of the inhibition of IRF4, IRF2, and RelB expression. TSA mediates its effects by preventing the recruitment of RNA polymerase II to the promoter of STAT5 target genes and by inhibiting their expression. However, this drug did not affect STAT5A or STAT5B phosphorylation or DNA binding. These results in GM-CSF-treated macrophages reveal a relationship between histone deacetylase complexes and STAT5 in the regulation of gene expression.
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PMID:Deacetylase activity is required for STAT5-dependent GM-CSF functional activity in macrophages and differentiation to dendritic cells. 1842 9

Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, are crucial for homing and migration of multiple stem cell types. Their potential role in mediating bone marrow-derived mesenchymal stem cell (BMSC) migration in areas of myocardial infarction (MI) has not been demonstrated. In this study, rat heart MI was created by left coronary artery ligation, and green fluorescent protein-labeled BMSCs were directly infused into the left ventricular cavity. Reverse transcriptase-polymerase chain reaction and Western blot analysis showed that SDF-1 was predominantly localized in the MI lesion, and its levels peaked by 3 to 7 days and were maintained at least 14 days. Additionally, this was matched with increased accumulation of BMSCs and an improvement in cardiac function. Furthermore, this effect was blocked by the phosphoinositide 3-kinase inhibitor, LY294002. In vitro experiments showed that CXCR4 expression by BMSCs was elevated during hypoxia and SDF-1 induced a concentration-dependent migration of BMSCs. This migration was CXCR4-dependent as confirmed by its total inhibition by AMD3100, a CXCR4-specific antagonist. Migration was also almost completely blocked by LY294002. Analysis showed that phosphorylated Akt was highly increased in SDF-1-treated BMSCs. Together these results demonstrated that SDF-1/CXCR4 may mediate the migration of BMSCs toward heart MI through activation of PI3K/Akt.
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PMID:SDF-1/CXCR4-mediated migration of transplanted bone marrow stromal cells toward areas of heart myocardial infarction through activation of PI3K/Akt. 2017 8

The G protein-coupled delta opioid receptor (DOR) plays a critical role in pain control. Emerging evidence shows that DOR also plays a role in neuronal differentiation and survival. Nerve growth factor (NGF) is known to be critical for the development and maintenance of the central and peripheral nervous systems. Our previous studies have shown that sustained activation of NGF/PI3K/Akt/NF-kappaB signaling is essential for NGF-induced dor gene expression during neuronal differentiation and that the epigenetic modifications at histone 3 lysine 9 temporally correlate with the dor gene transcription. In this study, we cloned the rat dor gene promoter and identified an NGF-responsive region similar to that from the mouse dor gene promoter. We further identified p300, a known NF-kappaB binding partner with intrinsic histone acetyltransferase activity, to be dynamically associated with the dor gene. We also found that assembling of RNA polymerase II (Pol II) at the promoter took place before NGF stimulation, indicating that p300 could only interact with preassembled Pol II at the promoter after NGF stimulation. Taken together, these results implicate that preassembly of the Pol II preinitiation complex, sustained activation of PI3K/Akt/NF-kappaB signaling, and dynamic p300 association at the promoters sequentially is one of the mechanisms of induction of the late phase genes during NGF-induced neuronal differentiation.
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PMID:Dynamic association of p300 with the promoter of the G protein-coupled rat delta opioid receptor gene during NGF-induced neuronal differentiation. 2039 42

Deregulation of RNA polymerase III (Pol III) transcription enhances cellular tRNAs and 5S rRNA production, leading to an increase in translational capacity to promote cell proliferation, transformation and tumor formation. Phosphorylation of histone H3 (H3ph) is induced by tumor promoters (EGF, UV and TPA) and immediate early genes, such as c-myc, c-jun and c-fos. However, it remains to be determined whether H3ph is involved in RNA Pol III transcription. Here, we report that EGF strongly induced H3ph at serine 28 (H3S28ph). EGF significantly increased transcription of RNA Pol III-dependent genes (Pol III genes), tRNA(Leu), tRNA(Tyr), 5S rRNA and 7SL RNA. Inhibition of EGFR, but not PI3K, reduced both H3S28ph and tRNA(Leu) and 5S rRNA transcription. EGF enhanced occupancy of H3S28ph in the promoters of tRNA(Leu) and 5S rRNA. Further analysis indicates that EGF augmented cellular levels of protein and mRNA of TFIIIB subunits, Brf1 and TATA box-binding protein (TBP). Brf1 is a specific transcription factor for RNA Pol III genes. EGF enhanced occupancy of H3S28ph in the Brf1 and TBP promoters. Inhibition of H3S28ph by mutant H3S28A repressed Brf1, TBP and tRNA(Leu) and 5S rRNA expression and decreased occupancy of H3S28ph in their promoters. Reduction of Brf1 significantly decreased tRNA(Leu) and 5S rRNA transcription and repressed EGF-induced anchorage-independent growth. Blocking H3S28ph signaling by using mutant H3S28A reduced EGF-induced cell transformation. Together, these results indicate that EGF activates EGFR signaling to induce H3S28ph, which, in turn, upregulates tRNA(Leu) and 5S rRNA transcription through Brf1 and TBP and promotes cell transformation. The studies demonstrate that epigenetic modification of H3S28ph has a critical role in the activity of Pol III genes.
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PMID:Phosphorylation of histone H3 serine 28 modulates RNA polymerase III-dependent transcription. 2146 Aug 52


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