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PMID: 17418410 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity.

Cancer cell ·Vol. 11 ·No. 4 ·2007-04-00 ·Pages 335-47

Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC

Abstract

HIF-2alpha promotes von Hippel-Lindau (VHL)-deficient renal clear cell carcinoma (RCC) tumorigenesis, while HIF-1alpha inhibits RCC growth. As HIF-1alpha antagonizes c-Myc function, we hypothesized that HIF-2alpha might enhance c-Myc activity. We demonstrate here that HIF-2alpha promotes cell-cycle progression in hypoxic RCCs and multiple other cell lines. This correlates with enhanced c-Myc promoter binding, transcriptional effects on both activated and repressed target genes, and interactions with Sp1, Miz1, and Max. Finally, HIF-2alpha augments c-Myc transformation of primary mouse embryo fibroblasts (MEFs). Enhanced c-Myc activity likely contributes to HIF-2alpha-mediated neoplastic progression following loss of the VHL tumor suppressor and influences the behavior of hypoxic tumor cells.

MeSH Terms
Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism Basic Helix-Loop-Helix Transcription Factors Cell Cycle Cell Hypoxia Cell Proliferation Cells, Cultured Chromatin Immunoprecipitation Colonic Neoplasms/metabolism,pathology Embryo, Mammalian/cytology,metabolism Fibroblasts/cytology,metabolism Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit/pharmacology Mice Mice, Knockout NIH 3T3 Cells/metabolism Nuclear Proteins/metabolism Promoter Regions, Genetic Protein Inhibitors of Activated STAT/metabolism Proto-Oncogene Proteins c-myc/genetics,metabolism RNA, Messenger/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Sp1 Transcription Factor/metabolism Trans-Activators Transcription Factors/pharmacology Transcription, Genetic Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Chemicals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Basic Helix-Loop-Helix Transcription Factors HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Nuclear Proteins Protein Inhibitors of Activated STAT Proto-Oncogene Proteins c-myc RNA, Messenger Sp1 Transcription Factor Trans-Activators Transcription Factors Max protein, mouse endothelial PAS domain-containing protein 1 Miz1 protein, mouse Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Gordan John D
Abramson Family Cancer Research Institute, School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Bertout Jessica A
Hu Cheng-Jun
Diehl J Alan
Simon M Celeste
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1535-6108
DOI
10.1016/j.ccr.2007.02.006
Published
2007-04-00
Pages
335-47
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3145406
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NCI NIH HHS · P01 CA104838 · United States
NCI NIH HHS · CA104838 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2007.02.006 PMC Full Text View journal details
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