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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle
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Cell Hypoxia*
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Cell Proliferation*
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Cells, Cultured
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Chromatin Immunoprecipitation
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / pharmacology
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Mice
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Mice, Knockout
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NIH 3T3 Cells / metabolism
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Nuclear Proteins / metabolism
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Promoter Regions, Genetic
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Protein Inhibitors of Activated STAT / metabolism
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Proto-Oncogene Proteins c-myc / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sp1 Transcription Factor / metabolism
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Trans-Activators
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Transcription Factors / pharmacology*
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Transcription, Genetic*
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic Helix-Loop-Helix Transcription Factors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Protein Inhibitors of Activated STAT
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Sp1 Transcription Factor
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Trans-Activators
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Transcription Factors
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Max protein, mouse
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endothelial PAS domain-containing protein 1
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Miz1 protein, mouse
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein