Hypoxia-inducible factor-1alpha mediates hypoxia-induced delayed neuronal death that involves p53.
Hypoxia-induced delayed neuronal death is known to require de novo gene expression; however, the molecular mediators that are involved remain undefined. The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), in addition to promoting the expression of adaptive genes under conditions of hypoxia, has been implicated as being a necessary component in p53-mediated cell death in tumors. Using herpes amplicon-mediated gene transfer in cortical neuronal cultures, we demonstrate that delivery of a dominant-negative form of HIF-1alpha (HIFdn), capable of disrupting hypoxia-dependent transcription, reduces delayed neuronal death that follows hypoxic stress. In contrast, hypoxia-resistant p53-null primary cultures are not protected by HIFdn expression. These data indicate that, in hypoxic neurons, HIF-1alpha and p53 conspire to promote a pathological sequence resulting in cell death.
Halterman
M W
MW
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Miller
C C
CC
Federoff
H J
HJ
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005799:Genes, Dominant; D016158:Genes, p53; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors