Source:http://linkedlifedata.com/resource/pubmed/id/16543242
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rdf:type | |
lifeskim:mentions |
umls-concept:C0017262,
umls-concept:C0032214,
umls-concept:C0035820,
umls-concept:C0078058,
umls-concept:C0185117,
umls-concept:C0205360,
umls-concept:C0242184,
umls-concept:C0376571,
umls-concept:C0600138,
umls-concept:C0871261,
umls-concept:C0965644,
umls-concept:C1171892,
umls-concept:C1333897,
umls-concept:C1704632,
umls-concept:C1704838,
umls-concept:C1706817,
umls-concept:C1709059,
umls-concept:C1998811,
umls-concept:C2911684,
umls-concept:C2911692
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pubmed:issue |
19
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pubmed:dateCreated |
2006-5-8
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pubmed:abstractText |
A recent study of breast cancer patients with and without BRCA1 gene mutations found significantly lower levels of VEGF in serum from patients with BRCA1 mutations (Tarnowski, B., Chudecka-Glaz, A., Gorski, B., and Rzepka-Gorska, I. (2004) Breast Cancer Res. Treat. 88, 287-288). Here, we describe a possible mechanistic explanation for this correlation. Because hypoxia in tumors stimulates VEGF expression and secretion we hypothesized that altered BRCA1 protein levels in breast tumors could affect hypoxia-stimulated VEGF promoter activity. This possibility was tested in cells transfected with various combinations of expression plasmids for BRCA1, BRCA1 specific inhibitory RNAs (BRCA1-siRNAs), HIF-1alpha, and a VEGF promoter-reporter and then incubated in normoxia (21%, O2) or hypoxia (0.1%, O2). As predicted, increased BRCA1 levels enhanced both hypoxia-stimulated VEGF promoter activity and the amounts of VEGF mRNA, as determined by semiquantitative RT-PCR and quantitative real time PCR. Using the ChIP assay, we discovered that BRCA1 could be recruited to the endogenous human VEGF promoter along with HIF-1alpha following hypoxia. An interaction between BRCA1 and HIF-1alpha was found in human breast cancer cells. We also found that hypoxia-stimulated VEGF promoter activity and secretion was reduced in cells containing reduced amounts of endogenous BRCA1 protein (obtained by transfecting with BRCA1 siRNAs). A mechanistic explanation for these effects is provided by our finding a reduced half-life and reduced accumulation of HIF-1alpha in hypoxic cells transfected with BRCA1-siRNAs and that proteasome inhibitors blocked these effects of BRCA1-siRNAs. Thus, our results suggest that normal amounts of BRCA1 function in hypoxia to regulate HIF-1alpha stability, probably by interacting with HIF-1alpha.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/BRCA1 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/HIF1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1, alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Oxygen,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factor A
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0021-9258
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
12
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pubmed:volume |
281
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
13047-56
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:16543242-BRCA1 Protein,
pubmed-meshheading:16543242-Cell Line, Tumor,
pubmed-meshheading:16543242-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:16543242-Humans,
pubmed-meshheading:16543242-Hypoxia-Inducible Factor 1, alpha Subunit,
pubmed-meshheading:16543242-Oxygen,
pubmed-meshheading:16543242-Promoter Regions, Genetic,
pubmed-meshheading:16543242-Transcription, Genetic,
pubmed-meshheading:16543242-Vascular Endothelial Growth Factor A
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pubmed:year |
2006
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pubmed:articleTitle |
BRCA1 plays a role in the hypoxic response by regulating HIF-1alpha stability and by modulating vascular endothelial growth factor expression.
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pubmed:affiliation |
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057-1469, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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