title: Hypoxia-inducible factor-1 alpha (HIF-1 alpha) escapes O(2)-driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm.
abstract: Eukaryotic cells sense oxygen and adapt to hypoxia by regulating a number of genes. Hypoxia-inducible factor 1 (HIF-1) is the 'master' in this pleiotypic response. HIF-1 comprises two members of the basic helix--loop--helix transcription factor family, HIF-1 alpha and HIF-1 beta. The HIF-1 alpha protein is subject to drastic O(2)-dependent proteasomal control. However, the signalling components regulating the 'switch' for 'escaping' proteasomal degradation under hypoxia are still largely unknown. The rapid nuclear translocation of HIF-1 alpha could represent an efficient way to escape from this degradation. We therefore asked, where in the cell is HIF-1 alpha degraded? To address this question, we trapped HIF-1 alpha either in the cytoplasm, by fusing HIF-1 alpha to the cytoplasmic domain of the Na(+)-H(+) exchanger (NHE-1), or in the nucleus, by treatment with leptomycin B. Surprisingly, we found that HIF-1 alpha is stabilized by hypoxia and undergoes O(2)-dependent proteasomal degradation with an identical half-life (5--8 min) in both cellular compartments. Therefore, HIF-1 alpha entry into the nucleus is not, as proposed, a key event that controls its stability. This result markedly contrasts with the mechanism that controls p53 degradation via MDM2.
authors.affiliation: Institute of Signalling, Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, 33 Avenue Valombrose 06189 Nice, France.
authors.forename: E
authors.initials: E
authors.lastname: Berra
authors.forename: D
authors.initials: D
authors.lastname: Roux
authors.forename: D E
authors.initials: DE
authors.lastname: Richard
authors.forename: J
authors.initials: J
authors.lastname: Pouysségur
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002458:Cell Fractionation; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
chemical_list: D000903:Antibiotics, Antineoplastic; D015853:Cysteine Proteinase Inhibitors; D005231:Fatty Acids, Unsaturated; D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; D017923:Sodium-Hydrogen Exchangers; D014157:Transcription Factors; C069139:growth factor-activatable Na-H exchanger NHE-1; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen; D000111:Acetylcysteine; C038753:leptomycin B