Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia.
Under hypoxia, HIF-1alpha binds to aryl hydrocarbon receptor nuclear translocator (ARNT, also called HIF-1beta) to activate expression of genes important for cell survival. Alternatively, HIF-1alpha can bind to the tumor suppressor p53 and promote p53-dependent apoptosis. Here we show that the opposite functions of HIF-1alpha are distinguished by its phosphorylation status. Two distinguishable forms of HIF-1alpha, phosphorylated and dephosphorylated, were induced during hypoxia-induced apoptosis. The phosphorylated HIF-1alpha was the major form that bound to ARNT. Ectopically expressed ARNT was consistently able to enhance HIF-1alpha phosphorylation in a binding-dependent manner. In contrast, the dephosphorylated HIF-1alpha was the major form that bound to p53. Depletion of the dephosphorylated HIF-1alpha, by using the Hsp90 inhibitor geldanamycin A that had little effect on the phosphorylated HIF-1alpha expression, suppressed p53 induction and subsequent apoptosis. Depletion of dephosphorylated HIF-1alpha also prevented hypoxia-induced nuclear accumulation of HDM2, a negative regulator of p53. Our results indicate that the functions of HIF-1alpha varied with its phosphorylation status and that dephosphorylated HIF-1alpha mediated apoptosis by binding to and stabilizing p53.
Suzuki
H
H
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Tomida
A
A
Tsuruo
T
T
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D016227:Benzoquinones; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011809:Quinones / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*
C497396:ARNT protein, human; D016227:Benzoquinones; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011809:Quinones; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D020169:Caspases; C001277:geldanamycin