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p53 down-regulation: a new molecular mechanism involved in ischaemic preconditioning

Mocanu, MM; Yellon, DM; (2003) p53 down-regulation: a new molecular mechanism involved in ischaemic preconditioning. FEBS LETT , 555 (2) 302 - 306. 10.1016/S0014-5793(03)01260-2.

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Abstract

Ischaemic preconditioning is associated with the activation of prosurvival mechanisms. Here we demonstrate that following a preconditioning protocol, the proapoptotic p53 is inactivated possibly via phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-murine double minute 2 (Mdm2) phosphorylation. Our data show that in preconditioned hearts Mdm2 was significantly phosphorylated, and wortmannin (a PI3K inhibitor) abrogated this effect (Western blotting). Also in preconditioned hearts p53 was shown to be bound to phospho-Mdm2 (co-immunoprecipitation). Furthermore, pifithrin alpha (a p53 inhibitor), administered to isolated perfused hearts prior to ischaemia, significantly attenuated the infarction. In conclusion our results suggest that p53 is implicated in ischaemia/reperfusion injury and that preconditioning counterbalances this effect via PI3K-Akt-Mdm2 phosphorylation. (C) 2003 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

Type:Article
Title:p53 down-regulation: a new molecular mechanism involved in ischaemic preconditioning
DOI:10.1016/S0014-5793(03)01260-2
Keywords:phosphatidylinositol 3-kinase-Akt pathway, Mdm2 phosphorylation, p53 downregulation, myocardial ischemia, ischemic preconditioning, PROTEIN-KINASE-C, APOPTOSIS, DEATH, AKT, TRANSCRIPTION, PROTECTION, ACTIVATION, INHIBITOR, PATHWAY, MDM2
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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