HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity

We demonstrate here that hypoxia-inducible factors -2a promotes cell-cycle progression in hypoxic renal clear cell carcinoma and multiple other cell lines

John D. Gordan; Jessica A. Bertout; Cheng-Jun Hu; J. Alan Diehl; M. Celeste Simon

2007

Scholarcy highlights

  • Low oxygen levels are frequently encountered in solid tumors, and hypoxic stress responses have important effects on the natural history of disease
  • hypoxia-inducible factors-2a was detected in HCT116 cells, but at approximately 10% the levels observed in WT8 cells
  • To correlate these data with transcriptional targets, mRNA was extracted from cells grown at 21% or 0.5% O2 for 24, 48, and 72 hr and analyzed by quantitative real-time PCR
  • While HCT116 cells exhibited basal Oct4 expression, hypoxic induction of HIF-2a in these cells had no further effect on transcript levels, likely due to low HIF-2a protein levels
  • We found that HIF-2a promotes c-Myc transcriptional activity and cell-cycle progression in renal carcinoma cells, NIH3T3 cells, HEK293 cells, and embryonic epithelial cells
  • When the WT8 cells were grown at 0.5% O2, statistically significant increases in the percentage of cells in S phase and decreases in the percentage in G1 phase after 24, 48, or 72 hr were observed
  • HIF-2a activation of these targets is not responsible for transformation in our study, as Oct4 and TGF-a were not detected in transformed mouse embryo fibroblasts cell lines or NIH3T3 cells described above, and similar mRNA and protein levels were observed for Cyclin D1 regardless of HIF-a expression
  • Enhanced c-Myc activity likely contributes to hypoxia-inducible factors-2a-mediated neoplastic progression following loss of the von Hippel-Lindau tumor suppressor and influences the behavior of hypoxic tumor cells

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