Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischaemia.
p53, a tumour suppressor, is involved in DNA repair and cell death processes and mediates apoptosis in response to death stimuli by transcriptional activation of pro-apoptotic genes and by transcription-independent mechanisms. In the latter process, p53 induces permeabilization of the outer mitochondrial membrane by forming an inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release in several cell line systems. However, it is unclear how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischaemia. We examined interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons using a tGCI (transient global cerebral ischaemia) rat model. We showed mitochondrial translocation of p53 and its binding to Bcl-X(L). Mitochondrial p53 translocation, interaction between p53 and Bcl-X(L), and cytochrome c release from mitochondria and subsequent CA1 neuronal death were prevented by pifithrin-alpha, a p53-specific inhibitor. These results suggest that the mitochondrial p53 pathway plays a role in delayed CA1 neuronal death after tGCI.
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Department of Neurosurgery, Stanford University School of Medicine, 1201 Welch Road, MSLS #P314, Stanford, CA 94305-5487, USA.
Saito
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A
Chan
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PH
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D017966:Pyramidal Cells / Q000473:pathology*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53