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

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.

SUBMITTER: Gordan JD

PROVIDER: S-EPMC3145406 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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

Gordan John D JD Bertout Jessica A JA Hu Cheng-Jun CJ Diehl J Alan JA Simon M Celeste MC

Cancer cell 20070401 4

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 ...[more]

PMID: 17418410

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