This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Berger, M. Articles by Haupt, Y. Search for Related Content PubMed PubMed Citation Articles by Berger, M. Articles by Haupt, Y.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2005, p. 5380-5388, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5380-5388.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel,¹ Laboratorio Nazionale CIB, AREA Science Park, Padriciano 99, and Dipartimento di Biochimica Biofisica Chimica delle Macromolecole, Via L. Giorgeri 1, 34023 Trieste, Italy²

Received 10 February 2005/ Returned for modification 21 March 2005/ Accepted 30 March 2005

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.

This article has been cited by other articles:

• Toledo, F., Lee, C. J., Krummel, K. A., Rodewald, L.-W., Liu, C.-W., Wahl, G. M. (2007). Mouse Mutants Reveal that Putative Protein Interaction Sites in the p53 Proline-Rich Domain Are Dispensable for Tumor Suppression. Mol. Cell. Biol. 27: 1425-1432 [Abstract] [Full Text]  
• Lacroix, M., Toillon, R.-A., Leclercq, G. (2006). p53 and breast cancer, an update.. Endocr Relat Cancer 13: 293-325 [Abstract] [Full Text]  
• Gueven, N., Becherel, O. J., Birrell, G., Chen, P., DelSal, G., Carney, J. P., Grattan-Smith, P., Lavin, M. F. (2006). Defective p53 Response and Apoptosis Associated with an Ataxia-Telangiectasia-like Phenotype.. Cancer Res. 66: 2907-2912 [Abstract] [Full Text]