Abstract
Many molecular and physiological responses to hypoxia in mammals are controlled by the transcription factors Hypoxia-Inducible Factor-1alpha (HIF-1alpha) and HIF-2alpha. 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-alpha are required for targeting HIF-alpha 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-alpha is thus stabilized and competent for transcription. Because these proteins participate in angiogenesis, glycolysis, programmed cell death, cancer, and ischemia, HIF-alpha and its mediators are attractive therapeutic targets.
MeSH terms
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Animals
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Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
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Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
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Asparagine / metabolism
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Gene Expression Regulation*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Oxygen / metabolism
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Procollagen-Proline Dioxygenase / genetics
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Procollagen-Proline Dioxygenase / metabolism
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Proline / metabolism
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Transcription, Genetic
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Substances
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ARNT protein, human
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Basic Helix-Loop-Helix Transcription Factors
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Hypoxia-Inducible Factor 1, alpha Subunit
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Aryl Hydrocarbon Receptor Nuclear Translocator
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endothelial PAS domain-containing protein 1
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Asparagine
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Proline
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Procollagen-Proline Dioxygenase
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Von Hippel-Lindau Tumor Suppressor Protein
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Oxygen