Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of the Rhox homeobox gene cluster on the X chromosome opens up new vistas in the regulation of reproductive processes in mammals. In mice, this cluster comprises more than 30 genes that are selectively expressed in reproductive tissues. A subset of Rhox genes are androgen and AR regulated in postnatal and adult Sertoli cells, making them candidates to mediate androgen-dependent steps during spermatogenesis. The best characterized of these androgen/AR-regulated genes is Rhox5 (Pem), the founding member of the Rhox gene cluster. Targeted deletion of Rhox5 in mice causes male subfertility marked by increased germ-cell apoptosis and decreased sperm count and motility. Microarray analyses identified a wide variety of genes regulated by Rhox5 in Sertoli cells. One of them is the tumour suppressor UNC5C, a pro-apoptotic molecule previously only known to be involved in brain development. Targeted deletion of Unc5c causes decreased germ-cell apoptosis in postnatal and adult testes, indicating that it also has a role in spermatogenesis and supporting a model in which Rhox5 promotes germ-cell survival by downregulating Unc5c. Rhox5 has two independently regulated promoters that have distinct expression patterns. The unique tissue-specific and developmentally regulated transcription pattern of these two promoters appear to be controlled by DNA methylation. Both promoters are methylated in tissues in which they are not expressed, suggesting that DNA methylation serves to repress Rhox5 expression in inappropriate cell types and tissues. In summary, the Rhox gene cluster is an epigenetically regulated set of genes encoding a large number of transcription factors that are strong candidates to regulate gametogenesis and other aspects of reproduction.
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PMID:Epigenetic regulation and downstream targets of the Rhox5 homeobox gene. 1863 53

Inappropriate gene silencing and subsequent promiscuous activity define the transformation of many solid tumours including renal cell carcinoma (RCC). Here, we report that UNC5C, one of the Netrin-1 receptors, was frequently inactivated in RCC cell lines and primary tumours. UNC5C protein was expressed in the proximal convoluted tubules of the human kidney, the presumed origin of clear cell RCC (ccRCC) and papillary RCC (pRCC). Compared to paired adjacent non-malignant tissues, both UNC5C mRNA and protein expression were significantly down-regulated in RCC. Immunohistochemical analysis showed that UNC5C was inactivated in 94.3% of the samples and the loss of UNC5C occurred at the early stage of RCC. Methylation specific PCR showed that UNC5C promoter was methylated in two renal carcinoma cell lines. Pharmacologic demethylation alone or in combination with inhibition of deacetylation dramatically induced UNC5C expression. Furthermore, bisulfite genomic sequencing (BGS) confirmed that dense methylation existed in UNC5C promoter. In paired tumour samples, UNC5C methylation was observed in 12 out of 44 patients (27.3%). Moreover, we analysed the loss of heterozygosity (LOH) of UNC5C in renal cell carcinoma, the LOH was observed in 27 out of 44 patients (61.4%). Finally, restoration of UNC5C expression suppressed the colony formation of renal carcinoma cells. In addition, UNC5C inhibited tumour cell proliferation, migration and enhanced chemosensitivity to cisplatin and etoposide. Therefore, UNC5C acts as a tumour suppressor in RCC and is down-regulated in RCC. Loss of heterozygosity and DNA methylation contribute to the inactivation of UNC5C in renal cell carcinoma.
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PMID:Genetic and epigenetic control of UNC5C expression in human renal cell carcinoma. 2160 Jul 61

Prostate cancer, the most common male cancer in Western countries, is commonly detected with complex chromosomal rearrangements. Following the discovery of the recurrent TMPRSS2:ETS fusions in prostate cancer and EML4:ALK in non-small-cell lung cancer, it is now accepted that fusion genes not only are the hallmark of haematological malignancies and sarcomas, but also play an important role in epithelial cell carcinogenesis. However, previous studies aiming to identify fusion genes in prostate cancer were mainly focused on expression changes and fusion transcripts. To investigate the genes recurrently affected by the chromosome breakpoints in prostate cancer, we analysed Affymetrix array 6.0 and 500K SNP microarray data from 77 prostate cancer samples. While the two genes most frequently affected by genomic breakpoints were, as expected, ERG and TMPRSS2, surprisingly more known tumour suppressor genes (TSGs) than known oncogenes were identified at recurrent chromosome breakpoints. Certain well-characterised TSGs, including p53, PTEN, BRCA1 and BRCA2 are recurrently truncated as a result of chromosome rearrangements in prostate cancer. Interestingly, many of the genes residing at recurrent breakpoint sites have not yet been implicated in prostate carcinogenesis such as HOOK3, PPP2R2A and TCBA1. We have confirmed the generally reduced expression of selected genes in clinical samples using quantitative RT-PCR analysis. Subsequently, we further investigated the genes associated with the t(4:6) translocation in LNCaP cells and reveal the genomic fusion of SNX9 and putative TSG UNC5C, which led to the reduced expression of both genes. This study reveals another common mechanism that leads to the inactivation of TSGs in prostate cancer and the identification of multiple TSGs inactivated by chromosome rearrangements will lead to new direction of research for the molecular basis of prostate carcinogenesis.
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PMID:Chromosome rearrangement associated inactivation of tumour suppressor genes in prostate cancer. 2199 1