Mutations in Proline 82 of p53 Impair Its Activation by Pin1 and Chk2 in Response to DNA Damage

Abstract

Tumor suppression by the p53 protein largely depends on the elimination of damaged cells by apoptosis. Mutations in the polyproline region (PPR) of p53 impair its apoptotic function. Deletion of the PPR renders p53 more sensitive to inhibition by Mdm2 via an unknown mechanism. We have explored the mechanism by which the PPR modulates the p53/Mdm2 loop. Proline 82 of p53 was identified to be essential for its interaction with the checkpoint kinase 2 (Chk2) and consequent phosphorylation of p53 on serine 20, following DNA damage. These physical and functional interactions are regulated by Pin1 through cis-trans isomerization of proline 82. Our study unravels the pathway by which Pin1 activates p53 in response to DNA damage and explains how Pin1 protects p53 from Mdm2. Further, we propose a role for Pin1-dependent induction of p53 conformational change as a mechanism responsible for the enhanced interaction between p53 and Chk2 following DNA damage. Importantly, our findings elucidate the selection for mutations in the Pin1 target Thr81/Pro82 motif within the PPR of p53 in human cancer.

ACKNOWLEDGMENTS

We are grateful to Sue Haupt for critical comments. We thank Matthias Dobbelstein, Thanos Halazonetis, Moshe Oren, and Arnie Levine for the generous gifts of plasmids.

This work was supported by grants from the Israel Science Foundation, the Israel Cancer Research Fund, the Israel Cancer Association, the German-Israeli Foundation for Scientific Research and Development, the Association for International Cancer Research, and EC FP6 funding (contract 503576).