Abstract
Hypoxia-inducible factor (HIF) is a master transcriptional regulator of hypoxia-inducible genes and consists of a labile alpha subunit (such as HIF1alpha) and a stable beta subunit (such as HIF1beta or ARNT). In the presence of oxygen, HIFalpha family members are hydroxylated on one of two conserved prolyl residues by members of the egg-laying-defective nine (EGLN) family. Prolyl hydroxylation generates a binding site for a ubiquitin ligase complex containing the von Hippel-Lindau (VHL) tumor suppressor protein, which results in HIFalpha destruction. In addition, the HIFalpha transcriptional activation function is modulated further by asparagine hydroxylation by FIH (factor-inhibiting HIF), which affects recruitment of the coactivators p300 and CBP. These findings provide new mechanistic insights into oxygen sensing by metazoans and are the first examples of protein hydroxylation being used in intracellular signaling. The existence of three human EGLN family members, as well as other putative hydroxylases, raises the possibility that this signal is used in other contexts by other proteins.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
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Review
MeSH terms
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Animals
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dioxygenases
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Gene Expression Regulation
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Humans
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Hydroxylation
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Immediate-Early Proteins / chemistry
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism
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Models, Biological
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Models, Molecular
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Multiprotein Complexes
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Procollagen-Proline Dioxygenase / chemistry
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Procollagen-Proline Dioxygenase / genetics
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Procollagen-Proline Dioxygenase / metabolism
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Proline / chemistry*
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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DNA-Binding Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immediate-Early Proteins
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Multiprotein Complexes
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Nuclear Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Proline
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Dioxygenases
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EGLN1 protein, human
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Procollagen-Proline Dioxygenase
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EGLN2 protein, human
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EGLN3 protein, human
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human