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 RIS Download
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