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

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.

Pubmed ID: 17418410


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


Cancer cell

Publication Data

April 9, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA104838
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle
  • Cell Hypoxia
  • Cell Proliferation
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Colonic Neoplasms
  • Embryo, Mammalian
  • Fibroblasts
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Protein Inhibitors of Activated STAT
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sp1 Transcription Factor
  • Trans-Activators
  • Transcription Factors
  • Transcription, Genetic
  • Von Hippel-Lindau Tumor Suppressor Protein