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)

We have established a cultured cell line named FU-UR-1 from a large retroperitoneal tumor of a 24-year-old Japanese male patient who simultaneously had a small renal cell carcinoma (RCC). Cytogenetic analysis and fluorescence in situ hybridization of the retroperitoneal tumor, and the cell line established from this tumor demonstrated similar karyotypes including add(13)(p11).ish der(13)t(13;17) (p11;q11)t(X;17)(p11;q25)(wcpX+,wcp17+). FU-UR-1 had been propagated continuously for more than 70 passages, and the doubling time was 32 h. Successful heterotransplantation was performed by inoculation of the cultured FU-UR-1 cells into the subcutis of BALB/c nude mice. Reverse transcriptase-polymerase chain reaction (RT-PCR) and sequence analysis demonstrated reciprocal ASPL-TFE3 and TFE3-ASPL fusion transcripts in the retroperitoneal tumor, cultured FU-UR-1 cells and xenografted tumors. In addition, the pathological findings of these samples and the renal tumor resembled each other. These observations suggest that the FU-UR-1 cell line established from the retroperitoneal tumor is an RCC cell line. This well-examined cell line may become a useful system for studying the genetic and biologic characteristics of rare neoplasms with the reciprocal ASPL-TFE3 fusion transcript.
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PMID:Establishment and characterization of a renal cell carcinoma cell line (FU-UR-1) with the reciprocal ASPL-TFE3 fusion transcript. 1513 51

Yeast Gtr1p and its human homolog RRAG A belong to the Ras-like small G-protein superfamily and genetically interact with RCC1, a guanine nucleotide exchange factor for Ran GTPase. Little is known regarding the function of Gtr1p. We performed yeast two-hybrid screening using Gtr1p as the bait to find interacting proteins. Rpc19p, a shared subunit of RNA polymerases I and III, associated with Gtr1p. The association of Gtr1p with Rpc19p occurred in a GTP-form-specific manner. RRAG A associated with RPA16 (human Rpc19p homolog) in a GTP-form-specific manner, suggesting that the association is conserved during evolution. Ribosomal RNA and tRNA synthesis were reduced in the gtr1Delta strain expressing the GDP form of Gtr1p, but not the GTP form of Gtr1p. Gel-filtration studies revealed an accumulation of the smaller Rpc19p-containing complex, but not of A135, in the gtr1Delta strain. Here, we propose that Gtr1p is involved in RNA polymerase I and III assembly by its association with Rpc19p and could be a mediator that links growth regulatory signals with ribosome biogenesis.
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PMID:Association of the GTP-binding protein Gtr1p with Rpc19p, a shared subunit of RNA polymerase I and III in yeast Saccharomyces cerevisiae. 1593 28

Short hairpin RNAs (shRNAs) transcribed by RNA polymerase III promoters can trigger sequence-selective gene silencing in mammalian cells. By virtue of their excellent function in knocking down expression of cancer-associated genes, shRNAs could be used as new therapeutic agents for cancer. As overexpression of Ki67 in renal cancer has been correlated to a more aggressive tumor phenotype, inhibition of Ki67 protein expression by means of shRNAs seems to be a promising approach for the therapy of renal cancer. In this study, we constructed an expression plasmid encoding shRNAs against the Ki67 gene, named pSilencerKi67, and transfected it into human renal carcinoma cells. The pSilencerKi67 was shown to significantly knock down the expression of the Ki67 gene in human renal carcinoma cells, resulting in inhibiting proliferation and inducing apoptotic cell death that can be maintained for at least 6 d. These findings offer the promise of using vector-based shRNAs against Ki67 in renal cancer gene therapy.
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PMID:Treatment with vector-expressed small hairpin RNAs against Ki67 RNA-induced cell growth inhibition and apoptosis in human renal carcinoma cells. 1660 65

Hypoxia inducible factor (HIF), a master regulator of critical genes for cell survival under hypoxic conditions, is known to be related to tumorigenesis and progression of renal cell carcinoma. N-methylpyrrole (Py)-N-methylimidazole (Im) hairpin polyamides are synthetic organic compounds that recognize and bind to the minor grooves of specific DNA sequences. We synthesized three Py-Im hairpin polyamides targeting the flanking sequences of hypoxia responsive element (HRE; a binding site of HIF) in the promoter region of the vascular endothelial growth factor (VEGF) gene. The effects of the polyamides on HIF-induced transcription were evaluated by a luciferase assay using a reporter plasmid containing a VEGF promoter. Real time reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay were performed to examine the effects of the polyamides on the transcription and secretion of VEGF in A498 renal cell carcinoma cells, which have a frame-shift mutation in the von Hippel-Lindau gene. A combination of three Py-Im hairpin polyamides suppressed HIF-induced transcription in reporter assays using 293 cells and successfully suppressed transcription and translation of the VEGF gene in A498 cells. Inhibition of the HIF-HRE interaction was confirmed by an electrophoresis mobility shift assay. An approach using Py-Im hairpin polyamides may be a new strategy for the treatment of renal cell carcinoma.
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PMID:Suppression of VEGF transcription in renal cell carcinoma cells by pyrrole-imidazole hairpin polyamides targeting the hypoxia responsive element. 1664 75

Niban is a recently identified molecular marker of renal carcinogenesis in the Tsc2 gene-mutant Eker rat. Niban expression is most dramatically increased in the early stage of renal carcinogenesis and might decline during malignant progression. Niban is also expressed in various histologic types of human renal cell carcinoma. Therefore, Niban might be a good marker for renal carcinogenesis in both animal models and humans. In the present study, we examined Niban expression in various thyroid lesions by immunohistochemical staining using polyclonal rabbit antihuman Niban antibody. Normal thyroid tissue never stained for Niban. Niban was most frequently expressed in tumors with oxyphilic cytoplasm, including oxyphilic variants of papillary carcinoma (4/4 = 100%), oxyphilic variants of follicular adenoma (7/7 = 100%), and oxyphilic variants of follicular carcinoma (5/5 = 100%). Eighty-one percent (44/54) of papillary carcinoma cases, including microcarcinomas, and follicular variants were also positively stained for Niban at variable intensities. Follicular carcinomas were less frequently and less intensely stained. In nonneoplastic lesions, cells were rarely positively stained. In Hashimoto's thyroiditis, scattered cells with oxyphilic cell metaplasia were weakly Niban-positive. Reverse transcriptase-polymerase chain reaction and Western blot analysis of frozen tissue confirmed Niban expression at the molecular level in 4 cases of papillary carcinoma. Taken together, Niban expression is up-regulated in various types of thyroid tumors. We postulate that Niban expression may play an important role in the tumorigenic process of the thyroid in several scenarios. (1) Niban expression may be closely related to the carcinogenic process, especially from the early stage of papillary thyroid carcinoma. (2) Niban may be closely associated with altered mitochondrial functions in preneoplastic and neoplastic processes of the thyroid. (3) Niban may be a molecular marker of the oxyphilic phenotype under various conditions. Further functional studies of Niban will clarify the role of Niban in various thyroid lesions.
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PMID:A novel tumor marker, Niban, is expressed in subsets of thyroid tumors and Hashimoto's thyroiditis. 1694 43

The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic alpha subunit of hypoxia-inducible factor (HIF) for oxygen-dependent destruction. Although emerging evidence supports the notion that deregulated accumulation of HIF upon the loss of VHL is crucial for the development of clear-cell renal cell carcinoma (CC-RCC), the molecular events downstream of HIF governing renal oncogenesis remain unclear. Here, we show that the expression of a homophilic adhesion molecule, E-cadherin, a major constituent of epithelial cell junctions whose loss is associated with the progression of epithelial cancers, is significantly down-regulated in primary CC-RCC and CC-RCC cell lines devoid of VHL. Reintroduction of wild-type VHL in CC-RCC (VHL(-/-)) cells markedly reduced the expression of E2 box-dependent E-cadherin-specific transcriptional repressors Snail and SIP1 and concomitantly restored E-cadherin expression. RNA interference-mediated knockdown of HIFalpha in CC-RCC (VHL(-/-)) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutants incapable of promoting HIFalpha degradation attenuated E-cadherin expression, correlating with the disengagement of RNA polymerase II from the endogenous E-cadherin promoter/gene. These findings reveal a critical HIF-dependent molecular pathway connecting VHL, an established "gatekeeper" of the renal epithelium, with a major epithelial tumor suppressor, E-cadherin.
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PMID:VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. 1706 Apr 62

Reverse transcriptase (RT) inhibitors are emerging as a novel class of anticancer differentiating agents, active in several human tumor cell models, such as melanoma and prostate, thyroid and colon carcinoma. Indeed, much evidence suggests that they may act by inhibiting endogenous RT, a gene highly expressed in undifferentiated and transformed cells. We therefore evaluated whether endogenous RT may represent a new molecular target in the treatment of human renal clear-cell carcinoma, a neoplasm with very low sensitivity to standard pharmacological therapies. Efavirenz and nevirapine, 2 non-nucleosidic RT inhibitors commonly used in HIV patients, either induced a reversible downregulation of cell proliferation or enhanced cell differentiation in primary cultures of human renal carcinoma cells characterized by high levels of endogenous RT activity. Both agents upregulated the expression of the vitamin D receptor and calbindin 28k genes, which are constitutively expressed in renal tubular cells, and induced vitamin D signaling by enhancing the ability of tumor cells to upregulate the vitamin D-dependent gene, CYP24. Furthermore, efavirenz- and nevirapine-differentiated tumor cells exhibited an immunogenic phenotype with an increased expression of HLA-I and CD40 antigens and an enhanced ability to elicit a specific T-cell response in mixed lymphocyte/tumor-cell cultures. Indeed, renal carcinoma cells exposed to efavirenz induced a CD8(+)CCR7-CD45RA(-) effector memory T-cell phenotype, whereas untreated RCC cells induced a CD8(+)CCR7(+)CD45RA(-) central memory T-cell phenotype. These data suggest that RT inhibitors may be a novel tool in the treatment of human renal clear-cell carcinoma, potentially able to enhance the immunogenic potential of tumor cell.
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PMID:Reverse transcriptase inhibitors induce cell differentiation and enhance the immunogenic phenotype in human renal clear-cell carcinoma. 1835 78

Coactivator activator (CoAA) has been reported to be a coactivator that regulates steroid receptor-mediated transcription and alternative RNA splicing. Herein, we show that CoAA is a dual-function coregulator that inhibits G(1)-S transition in human kidney cells and suppresses anchorage-independent growth and xenograft tumor formation. Suppression occurs in part by down-regulating c-myc and its downstream effectors ccnd1 and skp2 and causing accumulation of p27/Kip1 protein. In this cellular setting, CoAA directly represses the proto-oncogene c-myc by recruiting HDAC3 protein and decreasing both the acetylation of histone H3 and the presence of RNA polymerase II on the c-myc promoter. Interestingly, a splicing isoform of CoAA, coactivator modulator (CoAM), antagonizes CoAA-induced G(1)-S transition and growth inhibition by negatively regulating the mRNA levels of the endogenous CoAA isoform. In addition, we found that expression of CoAA protein is significantly decreased in human renal cell carcinoma compared with normal kidney. Our study presents evidence that CoAA is a potential tumor suppressor in renal carcinoma and that CoAM is a counterbalancing splice isoform. This is, thus far, the only example of a nuclear receptor coregulator involved in suppression of kidney cancer and suggests potentially significant new roles for coregulators in renal cancer biology.
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PMID:Dual roles for coactivator activator and its counterbalancing isoform coactivator modulator in human kidney cell tumorigenesis. 1882 45

BTG3/ANA/APRO4 has been reported to be a tumor suppressor gene in some malignancies. It constitutes important negative regulatory mechanism for Src-mediated signaling, a negative regulator of the cell cycle and inhibits transcription factor E2F1. We report that BTG3 is downregulated in renal cancer and that the mechanism of inactivation is through promoter hypermethylation. Quantitative real-time polymerase chain reaction (PCR) showed that BTG3 was downregulated in cancer tissues and cells. Genistein and 5-aza-2'-deoxycytidine (5Aza-C) induced BTG3 messenger RNA (mRNA) expression in A498, ACHN and HEK-293 renal cell carcinoma (RCC) cell lines. Bisulfite-modified PCR and DNA sequencing results showed complete methylation of BTG3 promoter in tumor samples and cancer cell lines. Genistein and 5Aza-C treatment significantly decreased promoter methylation, reactivating BTG3 expression. Chromatin immunoprecipitation assay revealed that genistein and 5Aza-C increased levels of acetylated histones 3, 4, 2H3K4, 3H3K4 and RNA polymerase II at the BTG3 promoter indicative of active histone modifications. Enzymatic assays showed genistein and 5Aza-C decreased DNA Methyltransferase, methyl-CpG-binding domain 2 activity and increased HAT activity. Cell cycle and 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide cell proliferation assays showed that genistein has antiproliferative effect on cancer cell growth through induction of cell cycle arrest. This is the first report to show that BTG3 is epigenetically silenced in RCC and can be reactivated by genistein-induced promoter demethylation and active histone modification. Genistein had similar effects to that of 5Aza-C, which is a potent demethylating agent with high toxicity and instability. Genistein being a natural, non-toxic, dietary isoflavone is effective in retarding the growth of RCC cells, making it a promising candidate for epigenetic therapy in renal carcinoma.
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PMID:BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. 1922 Oct

Both Xp11.2 translocation renal cell carcinoma (RCC) and alveolar soft part sarcoma (ASPS) are characterized by various translocations disrupting chromosome Xp11.2, which result in gene fusions involving the TFE3 transcription factor gene. Diagnostic tools to detect translocations involving the TFE3 gene on chromosome X would be valuable in the evaluation of these tumors. We developed a dual-color, break-apart fluorescence in situ hybridization (FISH) assay to identify the chromosomal break point in paraffin-embedded tissue. This assay was validated using 4 cases of Xp11.2 RCC [proven by karyotype and/or reverse-transcriptase polymerase chain reaction (RT-PCR)], 2 cases of ASPS (proven by karyotype or RT-PCR), the UOK109 cell line carrying the inv(X) (p11;q12), and several negative controls (both neoplastic and non-neoplastic). This break-apart FISH assay is a relatively quick procedure for detecting Xp11.2 RCC and ASPS translocations and can be applied to archival paraffin-embedded tissue.
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PMID:Dual-color, break-apart FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of Xp11 translocation renal cell carcinoma and alveolar soft part sarcoma. 2042 78


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