Regulation of Gene Expression by the Hypoxia-Inducible Factors

  1. Anthony O. Fedele,
  2. Murray L. Whitelaw and
  3. Daniel J. Peet
  1. Department of Molecular Biosciences (Biochemistry) and the Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia 5005 Australia


Many molecular and physiological responses to hypoxia in mammals are controlled by the transcription factors Hypoxia-Inducible Factor-1α (HIF-1α) and HIF-2α. Their ability to promote the transcription of hypoxia-inducible genes is mediated by protein stability and regulation of a C-terminal transactivation domain. Oxygen-dependent hydroxylation of conserved proline and asparagine residues in HIF-α are required for targeting HIF-α to proteasomes for destruction, and for inhibiting its capacity for CBP/p300-dependent transactivation, respectively. In hypoxia, the O2 required for prolyl and asparaginyl hydroxylation is limiting, and HIF-α is thus stabilized and competent for transcription. Because these proteins participate in angiogenesis, glycolysis, programmed cell death, cancer, and ischemia, HIF-α and its mediators are attractive therapeutic targets.

Graphic MRI slices of a hypoxic brain. Mike Smith and Bernie Dardzinski, Penn State University

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