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)

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.
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PMID:Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases. 1780 48

Apollon, a membrane-associated inhibitor of apoptosis protein, protects cells against apoptosis and is upregulated in certain tumor cells. In this study, the effects of Apollon protein knockdown by RNA interference on the growth of human HeLa, HT-1080 and MCF-7 cells in vitro and in vivo were investigated. An oncolytic adenovirus (ZD55) containing the RNA polymerase III-dependent U6 promoter to express short hairpin RNA (shRNA) directed against Apollon (ZD55-siApollon) was constructed. Our data show that ZD55-siApollon successfully exerts a gene knockdown effect and causes the inhibition of tumor cell growth both in culture and in athymic mice in vivo. Cell cycle analysis, 4',6-diamidino-2-phenylindole staining and western blot analysis reveal that ZD55-siApollon-mediated suppression of Apollon induces apoptosis. Intratumoral injection of ZD55-siApollon significantly inhibits tumor growth in HT-1080 xenograft mice. Furthermore, ZD55-siApollon enhances the antitumor effect of 5-fluorouracil, a chemotherapeutic agent. In conclusion, these results suggest that the depletion of Apollon by oncolytic adenovirus-shRNA delivery system provides a promising method for cancer therapy.
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PMID:Oncolytic adenovirus-mediated shRNA against Apollon inhibits tumor cell growth and enhances antitumor effect of 5-fluorouracil. 1823 5

Human renal clear cell carcinoma (RCC) is frequently associated with loss of the von Hippel-Lindau (VHL) tumor suppressor (pVHL), which inhibits ubiquitylation and degradation of the alpha subunits of hypoxia-inducible transcription factor. pVHL also ubiquitylates the large subunit of RNA polymerase II, Rpb1, phosphorylated on serine 5 (Ser5) within the C-terminal domain (CTD). A hydroxylated proline 1465 within an LXXLAP motif located N-terminal to the CTD allows the interaction of Rpb1 with pVHL. Here we report that in RCC cells, pVHL regulates expression of Rpb1 and is necessary for low-grade oxidative-stress-induced recruitment of Rpb1 to the DNA-engaged fraction and for its P1465 hydroxylation, phosphorylation, and nondegradative ubiquitylation. Egln-9-type prolyl hydroxylases, PHD1 and PHD2, coimmunoprecipitated with Rpb1 in the chromatin fraction of VHL(+) RCC cells in response to oxidative stress, and PHD1 was necessary for P1465 hydroxylation while PHD2 had an inhibitory effect. P1465 hydroxylation was required for oxidative-stress-induced Ser5 phosphorylation of Rpb1. Importantly, overexpression of wild-type Rpb1 stimulated formation of kidney tumors by VHL(+) cells, and this effect was abolished by P1465A mutation of Rpb1. These data indicate that through this novel pathway involving P1465 hydroxylation and Ser5 phosphorylation of Rbp1, pVHL may regulate tumor growth.
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PMID:The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. 1828 59

Cancer is one of the diseases for which RNA interference is a potential therapeutic approach. Genes involved in the promotion or maintenance of tumor growth are obvious targets for RNAi. RNAi is also considered an attractive additional approach to conventional chemotherapy for cancer treatment. Moreover, siRNAs have shown a high specificity for their molecular target mRNAs as they can selectively inhibit cancer-promoting genes that differ by a point mutation. Loss of heterozygosity (LOH) reduces genes to hemizygosity in cancer cells and presents an absolute difference between normal and cancer cells. The regions of LOH are usually much larger than the tumor suppressor gene, which is lost, and has been shown to contain genes that are essential for cell survival. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man. SNPs in essential genes that are frequently affected by LOH can be used as a target for a therapy against cancer cells with LOH. We have designed siRNAs against the gene of the large subunit of RNA polymerase II (POLR2A), a gene located in close proximity to the tumor suppressor gene p53, which frequently shows LOH in cancer cells. It is shown in vitro that siRNA can selectively inhibit POLR2A expression dependent on its genotype. Furthermore, cancer cell proliferation and tumor growth inhibition in nude mice was genotype dependent. We conclude that siRNA can be used for genotype-specific inhibition of tumor growth targeting an SNP in POLR2A in vivo.
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PMID:Allele-specific cancer cell killing in vitro and in vivo targeting a single-nucleotide polymorphism in POLR2A. 1916 36

Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC(50), 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC(50) range, 0.2-1.7 micromol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G(2)-M, S, and G(1) phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (maximum percentage tumor growth inhibition, range, 38-153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer(249)/Thr(252), for up to 16 hours following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise.
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PMID:AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. 1950 70

Cyclins and cyclin-dependent kinases (CDK) form a key part of the regulatory proteins that govern the cell cycle. Aberrancy in their function can lead to uncontrolled growth and proliferation of the cells which forms the basis of many human diseases, especially cancers. Seliciclib (CYC202, R-roscovitine) is a second-generation CDK inhibitor that competes for ATP binding sites on these kinases, reducing tumor growth and inducing cell death. It is a direct inhibitor of cyclin E/CDK2 and also has inhibitory effects on cyclin H/CDK7 and cyclin T/CDK9. Seliciclib leads to growth arrest and apoptosis of cell lines through activation of the p53 gene, inhibition of RNA processing and blockage of the RNA polymerase II-dependent transcription, and reduction of anti-apoptotic proteins. Seliciclib has good oral bioavailability, although its absorption is slowed by food. It is distributed rapidly to the body tissues and metabolized rapidly to a carboxylated derivative that is excreted by the kidneys. The major adverse effects of seliciclib are electrolyte disturbances (hypokalemia, hyponatremia), gastrointestinal side effects (nausea, emesis, anorexia), fatigue, transient hyperglycemia, elevation of liver enzymes and reversible elevation of serum creatinine. At present, it is in Phase II trials for non-small cell lung cancer and nasopharyngeal carcinoma.
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PMID:Seliciclib in malignancies. 1993 6

Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [(3)H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3beta (GSK-3beta) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3beta knockdown restored MM survival, suggesting the involvement of GSK-3beta in AT7519-induced apoptosis. GSK-3beta activation was independent of RNA pol II dephosphorylation confirmed by alpha-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3beta phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3beta in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM.
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PMID:AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition. 2010 Dec 21

Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastasis of non-small-cell lung cancer (NSCLC). The aim of this study was to develop an RNA-interference approach that targets VEGF, using a recombinant plasmid, and to explore its antitumor efficacy in NSCLC in vivo. shRNA-targeting VEGF was cloned into pGenesil-2 plasmid vector and then transfected into A549 human lung cancer cells, using cationic liposome. Reverse-transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analysis were used to evaluate the silencing effects of VEGF-shRNA on A549 cells in vitro. Further, the growth-inhibition capacity of VEGF-shRNA on A549 lung carcinoma xenografts was tested in nude mice. Proliferation, apoptosis, and angiogenesis in tumor tissues were measured by PCNA, TUNEL, and CD31 immunohistochemistry, respectively. shRNA-targeting VEGF significantly silenced VEGF expression in A549 lung cancer cells, as confirmed by RT-PCR and ELISA assay (P < 0.01). In vivo, the VEGF-shRNA delayed tumor growth and reduced tumor weight by approximately 61.96%, compared with control groups (P < 0.05), accompanied with angiogenesis inhibition (P < 0.01) and apoptosis induction (P < 0.01). Our data showed that the knockdown of VEGF by shRNA might be a potential therapeutic approach against human NSCLC.
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PMID:Efficient inhibition of non-small-cell lung cancer xenograft by systemic delivery of plasmid-encoding short-hairpin RNA targeting VEGF. 2018 98

Endothelial cells and endothelial cell precursors encoding a therapeutic gene have induced antitumor responses in preclinical models. Culture of peripheral blood provides a rich supply of autologous, highly proliferative endothelial cells, also referred to as blood outgrowth endothelial cells (BOECs). The aim of this study was to evaluate a novel antiangiogenic strategy using BOECs expressing fms-like tyrosine kinase-1 (sFlt1) and/or angiostatin-endostatin (AE) fusion protein. Conditioned medium from BOECs expressing sFlt1 or AE suppressed in vitro growth of pulmonary vein endothelial cells by 70% compared with conditioned medium from non-transduced BOEC controls. Reverse transcriptase-PCR analysis indicated that systemically administered BOECs proliferated in tumor tissue relative to other organs in C3(1)SV40 TAG transgenic (C3TAG) mice with spontaneous mammary tumors. Tumor volume was reduced by half in C3TAG mice and in mice bearing established lung or pancreatic tumors in response to the treatment with sFlt1-BOECs, AE-BOECs or their combination. Studies of tumor vascular density confirmed that angiogenic inhibition contributed to slowed tumor growth. In an orthotopic model of glioma, the median survival of mice treated with sFlt1-BOECs was double that of mice receiving no BOEC treatment (P=0.0130). These results indicate that further research is warranted to develop BOECs for clinical application.
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PMID:Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors. 2072

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that predisposes the affected individual to develop characteristic tumors. These include CNS hemangioblastoma, retinal angiomas, endolymphatic sac tumors, pancreatic cysts and tumors, epididymal cystadenomas, pheochromocytomas, renal cysts, and clear-cell renal carcinoma. The VHL gene was localized to 3p25 and then isolated by Latif et al. (1). The gene contains three exons with an open reading frame of 852 nucleotides, which encode a predicted protein of 284 amino acids. The VHL protein is believed to have several functions. It is involved in transcription regulation through its inhibition of elongation by binding to the B and C subunits of elongin. Mutations of VHL allow the B and C subunits to bind with the A subunit. This complex then overcomes "pausing" of RNA polymerase during mRNA transcription (2,3). Several studies suggest that the VHL protein is also involved in regulation of hypoxia-inducible transcripts, particularly vascular endothelial growth factor (VEGF), by altering mRNA stability (4,5). Therefore, VHL gene mutations permit the overexpression of VEGF under normoxic conditions, which leads to the angiogenesis believed to be required for tumor growth. The VHL-elongin BC complex (VBC) also binds two other proteins-CUL2 and Rbx1-in a complex that has structural similarity to other E3 ubiquitin ligase complexes (6). Such complexes mediate the degradation of cell-cycle regulatory proteins.
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PMID:Molecular analysis of the von hippel-lindau disease gene. 2131 97


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