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

FEBS Letters

Mocanu, Mihaela M¹  Yellon, Derek M¹ 

[1] The Hatter Institute and Centre for Cardiology, University College London Medical School, London WC1E 6DB, UK

关键词: Phosphatidylinositol 3-kinase-Akt pathway;    Mdm2 phosphorylation;    p53 downregulation;    Myocardial ischemia;    Ischemic preconditioning;    PI3K;    phosphatidylinositol 3-kinase;    Akt;    protein kinase B;    Mdm2;    murine double minute 2;   

DOI  :  10.1016/S0014-5793(03)01260-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 α (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.

【 授权许可】

Unknown