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Originally published In Press as doi:10.1074/jbc.C200538200 on October 17, 2002

J. Biol. Chem., Vol. 277, Issue 50, 47976-47979, December 13, 2002
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ACCELERATED PUBLICATION
Role of Pin1 in the Regulation of p53 Stability and p21 Transactivation, and Cell Cycle Checkpoints in Response to DNA Damage*

Gerburg M. WulfDagger , Yih-Cherng Liou§, Akihide Ryo, Sam W. Lee, and Kun Ping Lu||

From the Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

DNA damage leads to stabilization and accumulation of p53, which plays a pivotal role in transcriptional activation of p21 and cell cycle arrest. The increase in p53 stability depends critically on its phosphorylation on serine/threonine residues, including those preceding a proline (Ser(P)/Thr-Pro). The Ser(P)/Thr-Pro moiety exists in the two distinct cis and trans conformations and their conversion is catalyzed specifically by the prolyl isomerase Pin1. Pin1 regulates the conformation and function of certain phosphorylated proteins and plays an important role in cell cycle regulation, oncogenesis, and Alzheimer's disease. However, nothing is known about the role of Pin1 in DNA damage. Here we found that DNA damage enhanced the interaction between Pin1 and p53, which depended on the WW domain in Pin1 and Ser33/46-Pro motifs in p53. Furthermore, Pin1 regulates the stability of p53 and its transcriptional activity toward the p21 promoter. As a result, p53 and p21 barely increased after DNA damage in Pin1 knock-out embryonic fibroblasts or in neoplastic cells depleted of Pin1. Moreover, Pin1 null cells displayed significant defects in cell cycle checkpoints induced by DNA damage. These results demonstrate a new role of Pin1 in regulating p53 function during DNA damage.

* This work was supported in part by National Institutes of Health Grant GM58556 (to K. P. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of Mentored Clinical Scientist Award CA093655 from the National Institutes of Health.

§ A Canada Health Research Council Fellow.

A Leukemia and Lymphoma Society Special Fellow.

|| A Pew Scholar and a Leukemia and Lymphoma Society Scholar. To whom correspondence should be addressed: Beth Israel Deaconess Medical Center, 330 Brookline Ave., HIM 1047, Boston, MA 02215. Tel.: 617-667-4143; Fax: 617-667-0610; E-mail: klu@caregroup.harvard.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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