Physical and Functional Interaction between p53 and the Werner’s Syndrome Protein

doi:10.1074/jbc.274.41.29463

Physical and Functional Interaction between p53 and the Werner’s Syndrome Protein*

From the ^‡Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel, the ^§Veterans Affairs Medical Center, Seattle, Washington 98108, and the ^¶Departments of Medicine, Neurology, and Pharmacology, University of Washington, Seattle, Washington 98195

Abstract

Werner’s syndrome is a human autosomal recessive disorder leading to premature aging. The mutations responsible for this disorder have recently been localized to a gene (WRN) encoding a protein that possesses DNA helicase and exonuclease activities. Patients carrying WRN gene mutations exhibit an elevated rate of cancer, accompanied by increased genomic instability. The latter features are also characteristic of the loss of function of p53, a tumor suppressor that is very frequently inactivated in human cancer. Moreover, changes in the activity of p53 have been implicated in the onset of cellular replicative senescence. We report here that the WRN protein can form a specific physical interaction with p53. This interaction involves the carboxyl-terminal part of WRN and the extreme carboxyl terminus of p53, a region that plays an important role in regulating the functional state of p53. A small fraction of WRN can be found in complex with endogenous p53 in nontransfected cells. Overexpression of WRN leads to augmented p53-dependent transcriptional activity and induction of p21^Waf1 protein expression. These findings support the existence of a cross-talk between WRN and p53, which may be important for maintaining genomic integrity and for preventing the accumulation of aberrations that can give rise to premature senescence and cancer.

Footnotes

↵* This work was supported in part by United States Public Health Service Grant RO1 CA40099 from NCI (to M. O.), the Center for Excellence Program of the Israel Science Foundation (to M. O.), the German-Israeli Project Cooperation (DIP) (to M. O.), and Grant AG120192 from NIA (to G. D. S.).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.
↵‖ To whom correspondence should be addressed. Tel.: 972-8-9342358; Fax: 972-8-9465223; E-mail: lioren@wiccmail.weizmann.ac.il.
↵2 S.Wilder and M. Oren, unpublished data.
Abbreviations:

WT

wild-type

TFIIH

transcription factor IIH

PCR

polymerase chain reaction

GST

glutathione S-transferase

PAGE

polyacrylamide gel electrophoresis
- Received April 20, 1999.
- Revision received July 12, 1999.
The American Society for Biochemistry and Molecular Biology, Inc.