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.
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
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
Cancer Cell
Date: Apr. 01, 2007
PubMed ID: 17418410
View in: Pubmed Google Scholar
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