Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

UCN-01, a protein kinase C/cyclin-dependent kinase inhibitor, suppressed thymidylate synthase (TS) protein expression in a dose-dependent manner with near complete suppression at 1 microM after a 24-h exposure in human gastric cancer cell line SK-GT5. Other protein kinase C/cyclin-dependent kinase inhibitors, including flavopiridol and safingol, had a similar effect on TS protein expression, but to a lesser degree. Moreover, UCN-01 repressed the induction of TS after 5-fluorouracil (FU) exposure by 90-95% and significantly enhanced the induction of apoptosis by FU from 4-8% with either FU or UCN-01 alone to 46+/-1% (P < 0.005 versus either single drug, reverse sequence, or the combination) when UCN-01 was given after FU. The effect of UCN-01 on TS was associated with a dose-dependent suppression of the E2F-1 protein, a transcriptional activator of TS. Northern blot analysis revealed that TS mRNA levels decreased gradually as the concentration of UCN-01 increased, but that E2F-1 mRNA levels remained relatively unchanged. UCN-01 may provide a novel way to enhance cellular sensitivity toward FU by means of suppressing TS expression mediated mainly by down-regulation of E2F-1.
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PMID:UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. 974 40

A surprising finding in the report by Rahman et al. in this issue of Cancer Cell is that forced overexpression of human thymidylate synthase transforms immortalized murine cells into a malignant phenotype. We discuss the possibility that elevated levels of thymidylate synthase noted in some human malignancies may contribute to tumor progression and may also reflect increased levels of its transcriptional activator E2F-1.
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PMID:Thymidylate synthase as an oncogene? 1509 41

Transcription factor E2F-1 mediates apoptosis and suppresses tumorigenesis. The mechanisms by which E2F-1 functions in these processes are largely unclear. We report here that E2F-1 acts as a transcriptional regulator of MKP-2 (MAPK phosphatase-2), a dual specificity protein phosphatase (DUSP4) with stringent substrate specificity for MAPKs. We show that E2F-1 is required for the cellular apoptotic response to oxidative damage. MKP-2 is greatly increased following oxidative stress, and E2F-1 is necessary for that induction. We found that E2F-1 is physically associated with the MKP-2 promoter and can transactivate the promoter of the MKP-2 gene. Specifically, E2F-1 binds to a perfect palindromic motif in the MKP-2 promoter. Finally, we show that this E2F-1/MKP-2 pathway mediates apoptosis under oxidative stress and that MKP-2 suppresses tumor formation in nude mice. Our findings demonstrate that E2F-1 is a transcriptional activator of MKP-2 and that MKP-2 is an essential cell death mediator in the E2F-1 pathway. Characterization of MKP-2 as a cell death mediator may lead to the development of new strategies for cancer treatment.
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PMID:A molecular link between E2F-1 and the MAPK cascade. 1745 31

E2F-1 mediates apoptosis through transcriptional regulation of its targets. We report here that E2F-1 acts as a direct transcriptional regulator of dual specificity phosphatase 1 (DUSP1; CL100), a threonine and tyrosine phosphatase that inhibits mitogen-activated protein (MAP) kinases. We found that DUSP1 is transcriptionally induced by ectopic E2F-1 expression and that extracellular signal-regulated kinase 1/2 are dephosphorylated in the presence of E2F-1 and DUSP1. E2F-1 mediates apoptosis in the cellular response to oxidative stress. DUSP1 levels are significantly increased in an E2F-1-dependent manner following oxidative stress but not other stresses examined. DUSP1 mediates the cellular response to oxidative stress. We found that E2F-1 binds to chromatin encompassing the DUSP1 promoter and greatly stimulates the promoter activity of the DUSP1 gene. In particular, E2F-1 physically binds to an E2F-1 consensus sequence and a palindromic motif in the DUSP1 promoter. Interestingly, E2F-1 is acetylated following oxidative stress. Our findings show that E2F-1 is a transcriptional activator of DUSP1 and that DUSP1 is a link between E2F-1 and MAP kinases.
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PMID:Dual specificity phosphatase 1/CL100 is a direct transcriptional target of E2F-1 in the apoptotic response to oxidative stress. 1763 84

Rationale: Hyperlipidemia is a major risk factor of atherosclerosis and cardiovascular diseases (CVD). As a standard-of-care approach for hyperlipidemia, statins only reduce the risk of coronary artery disease by 20-40%, underscoring the importance of identifying molecular pathways for the design of drugs against this disorder. Alterations in microRNA (miRNA) expression have been reported in patients with hyperlipidemia and CVD. This study was designed to determine the mechanism of dysregulated miR-378a-3p under the status of hyperlipidemia and evaluate how miR-378a-3p regulates hepatic secretion of VLDL. Methods: Wild-type mice kept on a high fat diet were injected with miR-378a-3p inhibitor or a mini-circle expression system containing miR-378a precursor to study loss and gain-of functions of miR-378a-3p. Mice were treated with Triton WR1339 and 35S-methionine/cysteine to determine the effect of miR-378a-3p on hepatic secretion of VLDL. Database mining, luciferase assay, and ChIP (chromatin immunoprecipitation) were used to study the mechanism of dysregulated miR-378a-3p biogenesis. Results: miR-378a-3p expression is significantly increased in livers of hyperlipidemic mice. Sort1 (sortilin 1) was identified as a direct target of miR-378a-3p. By inhibiting the function of sortilin 1 as a transmembrane trafficking receptor, miR-378a-3p stabilized ApoB100 and promoted ApoB100 secretion in vitro. Liver-specific expression of miR-378a-3p stabilized ApoB100 and facilitated hepatic secretion of VLDL, which subsequently increased levels of VLDL/LDL cholesterol as well as triglycerides. In contrast, antagonizing miR-378a-3p using its inhibitor increased hepatic expression of Sort1 and reduced hepatic export of VLDL with its consequent effects of serum lipid levels. Additional knockdown of up-regulated Sort1 in livers of mice offset the effects of miR-378a-3p inhibitor, suggesting that Sort1 was indispensable for miR-378a-3p to promote secretion of VLDL and thereby high levels of circulating VLDL/LDL cholesterol and triglycerides. Furthermore, oncogenic E2F1 (E2F transcription factor 1) was identified as a transcriptional activator of miR-378a-3p. E2f1 knockdown, through reducing miR-378a-3p, impaired secretion of VLDL and reduced levels of VLDL/LDL cholesterol and triglycerides. Conclusions: This study defines a novel pathway of E2F1-miR-378a-3p-SORT1-ApoB100 that controls levels of circulating VLDL/LDL cholesterol and triglycerides by modulating degradation and secretion of ApoB100, and suggests the use of miR-378a-3p as a potential therapeutic target for dyslipidemia.
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PMID:Activation of microRNA-378a-3p biogenesis promotes hepatic secretion of VLDL and hyperlipidemia by modulating ApoB100-Sortilin1 axis. 3222 31