title: HIF-1alpha and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia.
abstract: Brain ischemia is a cause of substantial morbidity and mortality during the later decades of life. In light of this, many studies have used in vitro and in vivo models of acute necrosis to test candidate therapeutic agents. More recently, the existence of a genetically programmed component of ischemic death has become widely accepted. We have used molecular genetic approaches to investigate the potential link between hypoxia-induced gene transcription and the delayed death of ischemic neurons. Hypoxia-induced gene expression is an evolutionarily conserved response comprising both transcriptional activation and posttranscriptional and posttranslational stabilization events. Members of the PER-ARNT-SIM (PAS) family of basic helix-loop-helix transcription factors have been shown to regulate hypoxic transcripts in nonneuronal cultured lines. However, evidence for ischemic activation of PAS proteins within the neuronal compartment or possible involvement in neuronal death is lacking. The tumor-suppressor protein p53 is a known transcriptional activator within the central nervous system that is clearly involved in the pathologic response to ischemia. This article will provide data that implicate the coordinate activities of p53 and the PAS protein HIF-1alpha in driving ischemia-induced delayed neuronal death. Background regarding mechanisms of ischemic neuronal death will also be provided with special attention paid to the role of de novo gene expression in promoting this pathologic sequence. The identification of the HIF-1alpha/p53-mediated signaling pathway in neurons highlights a novel target toward which anti-ischemic neuroprotective drug discovery can be applied.
authors.affiliation: Department of Microbiology and Immunology, Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York, 14642, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Halterman
authors.forename: H J
authors.initials: HJ
authors.lastname: Federoff
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009336:Necrosis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53