HIF-2α promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity

被引:651
作者
Gordan, John D.
Bertout, Jessica A.
Hu, Cheng-Jun
Diehl, J. Alan
Simon, M. Celeste
机构
[1] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA
[4] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA
关键词
D O I
10.1016/j.ccr.2007.02.006
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
HIF-2 alpha promotes von Hippel-Lindau (VHL)-deficient renal clear cell carcinoma (RCC) tumorigenesis, while HIF-1 alpha inhibits RCC growth. As HIF-1 alpha antagonizes c-Myc function, we hypothesized that HIF-2 alpha might enhance c-Myc activity. We demonstrate here that HIF-2 alpha 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-2 alpha augments c-Myc transformation of primary mouse embryo fibroblasts (MEFs). Enhanced c-Myc activity likely contributes; to HIF-2 alpha-mediated neoplastic progression following loss of the VHL tumor suppressor and influences the behavior of hypoxic tumor cells.
引用
收藏
页码:335 / 347
页数:13
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