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.
Highlights
Mutational inactivation of the p53 tumor suppressor gene is a very common event in human cancer [1, 2]
The Werner’s syndrome protein (WRN) Protein Binds p53 in Vitro—The p53 protein can engage in a multitude of protein-protein interactions, some of which are known to modulate its activity in a variety of ways
The data presented in this study demonstrate that p53 and WRN can engage in a direct physical association, mediated through the C-terminal portion of WRN and the extreme Cterminal domain of p53
Summary
Vol 274, No 41, Issue of October 8, pp. 29463–29469, 1999 Printed in U.S.A. Physical and Functional Interaction between p53 and the Werner’s Syndrome Protein*. Overexpression of WRN leads to augmented p53-dependent transcriptional activity and induction of p21Waf 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. The fact that mutations in WRN predispose to accelerated aging implies that the WRN protein plays a critical role in preventing premature aging This conjecture gains further support from the observation that expression of WRN decreases in normal fibroblasts undergoing senescence in culture [33]. Overexpression of WRN results in elevated p53-dependent transcriptional activity This suggests that some of the cellular activities of WRN may involve a cross-talk with p53, perhaps as a means for maintaining genomic stability and preventing the accumulation of irreversible genetic damage that may eventually lead to loss of replicative capacity
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