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  Putatative Prostate Cancer Risk SNP in an Androgen Receptor-binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Bu, H., Narisu, N., Schlick, B., Rainer, J., Manke, T., Schäfer, G., et al. (2015). Putatative Prostate Cancer Risk SNP in an Androgen Receptor-binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites. Human Mutations, 37, 52-64. doi:doi: 10.1002/humu.22909.

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Bu, Huajie1, 2, Autor
Narisu, Narisu3, Autor
Schlick, Bettina1, 4, Autor
Rainer, Johannes5, 6, Autor
Manke, T.7, Autor           
Schäfer, Georg1, 8, Autor
Pasqualini, Lorenza1, Autor
Chines, Peter3, Autor
Schweiger, Michal R.9, 10, Autor
Fuchsberger, Christian6, 11, Autor
Klocker , Helmut1, Autor
Affiliations:
1Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsburck, Austria, ou_persistent22              
2Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria, ou_persistent22              
3Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethsda, Maryland, USA, ou_persistent22              
4Oncotyrol, Center for Personalized Cancer Medicine, Innsbruck, Austria, ou_persistent22              
5Biocenter Innsbruck, Section for Molecular Pathphysiology, Medical University of Innsbruck, Innsbruck, Austria, ou_persistent22              
6Center for Biomedicine EURAC Research, Bolzano, Italy, ou_persistent22              
7Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243644              
8Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria, ou_persistent22              
9Max Planck Institute for Molecular Genetics, Berlin, Germany, ou_persistent22              
10Cologne Center for Genomics, University of Cologne, Cologne, Germany, ou_persistent22              
11Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA, ou_persistent22              

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 Zusammenfassung: Genome-wide association studies have identified genomic loci, whose single-nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin-immunoprecipitation-coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor-binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH) was within a novel putative auxiliary AR-binding motif, which is enriched in the neighborhood of canonical androgen-responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of MLPH in primary prostate tumors was significantly lower in those with the G compared with the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favorable PCa risk profile points out a tumor-suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH.

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Sprache(n): eng - English
 Datum: 2015-01
 Publikationsstatus: Erschienen
 Seiten: 13
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: doi: 10.1002/humu.22909
 Art des Abschluß: -

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Titel: Human Mutations
  Andere : Hum Mut
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: New York, N.Y. : Wiley-Liss
Seiten: - Band / Heft: 37 Artikelnummer: - Start- / Endseite: 52 - 64 Identifikator: Anderer: 954925597586
ISSN: 1059-7794
CoNE: https://pure.mpg.de/cone/journals/resource/954925597586