HIF-1 alpha and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia

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 a nd in vivo models of acute necrosis to test candidate therapeutic agents. M ore recently the existence of a genetically programmed component of ischemi c death has become widely accepted. We have used molecular genetic approach es to investigate the potential link between hypoxia-induced gene transcrip tion and the delayed death of ischemic neurons. Hypoxia-induced gene expres sion is an evolutionarily conserved response comprising both transcriptiona l activation and posttranscriptional and posttranslational stabilization ev ents. Members of the PER-ARNT-SIM (PAS) family of basic helix-loop-helix tr anscription factors have been shown to regulate hypoxic transcripts in nonn euronal cultured lines. However, evidence for ischemic activation of PAS pr oteins within the neuronal compartment or possible involvement in neuronal death is lacking. The tumor-suppressor protein p53 is a known transcription al activator within the central nervous system that is clearly involved in the pathologic response to ischemia, This article will provide data that im plicate the coordinate activities of p53 and the PAS protein HIF-1 alpha in driving ischemia-induced delayed neuronal death. Background regarding mech anisms of ischemic neuronal death will also be provided with special attent ion paid to the role of de novo gene expression in promoting this pathologi c sequence, The identification of the HIF-1 alpha/p53-mediated signaling pa thway in neurons highlights a novel target toward which antiischemic neurop rotective drug discovery can be applied, (C) 1999 Academic Press.