| HEXIM1 modulates vascular endothelial growth factor expression and function in breast epithelial cells and mammary gland. | |
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MedLine Citation:
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PMID: 20453883 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Recently, we found that mutation of the C-terminus of transcription factor hexamethylene bisacetamide-inducible protein 1 (HEXIM1) in mice leads to abnormalities in cardiovascular development because of aberrant vascular endothelial growth factor (VEGF) expression. HEXIM1 regulation of some genes has also been shown to be positive transcription elongation factor b (P-TEFb) dependent. However, it is not known whether HEXIM1 regulates VEGF in the mammary gland. We demonstrate that HEXIM1 regulates estrogen-induced VEGF transcription through inhibition of estrogen receptor-alpha recruitment to the VEGF promoter in a P-TEFb-independent manner in MCF-7 cells. Under hypoxic conditions, HEXIM1 inhibits estrogen-induced hypoxia-inducible factor-1 alpha (HIF-1alpha) protein expression and recruitment of HIF-1alpha to the hypoxia-response element in the VEGF promoter. In the mouse mammary gland, increased HEXIM1 expression decreased estrogen-driven VEGF and HIF-1alpha expression. Conversely, a mutation in the C-terminus of HEXIM1 (HEXIM1(1-312)) led to increased VEGF and HIF-1alpha expression and vascularization in mammary glands of heterozygous HEXIM1(1-312) mice when compared with their wild-type littermates. In addition, HEXIM1(1-312) mice have a higher incidence of carcinogen-induced mammary tumors with increased vascularization, suggesting an inhibitory role for HEXIM1 during angiogenesis. Taken together, our data provide evidence to suggest a novel role for HEXIM1 in cancer progression. |
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Authors:
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N Ogba; Y Q Doughman; L J Chaplin; Y Hu; M Gargesha; M Watanabe; M M Montano |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-05-10 |
Journal Detail:
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Title: Oncogene Volume: 29 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-24 Completed Date: 2010-07-16 Revised Date: 2011-12-22 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 3639-49 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Rainbow Babies and Children's Hospital, Cleveland, OH, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carcinogens / toxicity Cell Hypoxia / drug effects Cell Line, Tumor Epithelial Cells / drug effects, metabolism*, pathology Estradiol / pharmacology Estrogen Receptor alpha / metabolism Gene Expression Regulation* Humans Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Mammary Glands, Animal / blood supply, drug effects, metabolism*, pathology Mammary Neoplasms, Experimental / chemically induced, metabolism, pathology, physiopathology Mice Mutation Neovascularization, Pathologic / metabolism Neovascularization, Physiologic Positive Transcriptional Elongation Factor B / metabolism Promoter Regions, Genetic / genetics RNA-Binding Proteins / chemistry, genetics, metabolism* Response Elements Vascular Endothelial Growth Factor A / genetics*, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA92440/CA/NCI NIH HHS; R01 CA092440-07/CA/NCI NIH HHS; R01 CA092440-10/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carcinogens; 0/Estrogen Receptor alpha; 0/HEXIM1 protein, human; 0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA-Binding Proteins; 0/Vascular Endothelial Growth Factor A; 50-28-2/Estradiol; EC 2.7.11.-/Positive Transcriptional Elongation Factor B |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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