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Department of Molecular Biosciences (Biochemistry) and the Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia 5005 Australia
MRI slices of a hypoxic brain. Mike Smith and Bernie Dardzinski, Penn State University
Many molecular and physiological responses to hypoxia in mammals are controlled by the transcription factors Hypoxia-Inducible Factor-1
(HIF-1) and HIF-2. 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- are required for targeting HIF- 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- is thus stabilized and competent for transcription. Because these proteins participate in angiogenesis, glycolysis, programmed cell death, cancer, and ischemia, HIF- and its mediators are attractive therapeutic targets.
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