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J. Biol. Chem., Vol. 280, Issue 17, 17329-17338, April 29, 2005

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Relief of p53-mediated Telomerase Suppression by p73^*

Wen Hong Toh, Satoru Kyo, and Kanaga Sabapathy¶||

From the Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, National Cancer Centre, 11, Hospital Drive, Singapore 169610, Singapore, the Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641, Japan, and the ^¶Department of Biochemistry, National University of Singapore, 10, Kent Ridge Crescent, Singapore 119260, Singapore

Reactivation of telomerase is a feature in many cancer cells. Telomerase activation inhibits telomere shortening, thereby preventing cell cycle arrest and apoptosis activated by shortened telomeres or chromosomal rearrangements. The tumor-suppressor gene product, p53, was previously shown to transcriptionally suppress the activation of the catalytic subunit of telomerase (hTERT). Here we have evaluated the role of p73 in hTERT regulation. We found that ectoptic expression of p73, in contrast to p73 or p53, in p53 null H1299 cells does not lead to suppression of hTERT transcription. However co-expression of p73 or p73 together with p53 abolished p53-mediated hTERT suppression. This phenomenon was found to be dependent on the DNA binding ability of p73. We also show that p53-mediated suppression of hTERT transcription requires a minimum threshold level of p53, and p73 abrogates p53-mediated suppression by reducing p53 levels through the activation of HDM2. Moreover, p53-mediated hTERT suppression was not relieved by p73 in cells depleted of HDM2 through small interfering RNA-mediated gene silencing. In addition, knockdown of HDM2 in MCF7 cells, which express moderately high levels of p73 and p53, resulted in the reduction of endogenous hTERT levels. Finally, knockdown of p73 in MCF7 cells resulted in increased p53 protein levels and a concomitant decrease in hTERT levels. Together, our data indicate a plausible way by which p73, through HDM2, can oppose p53 tumor suppressor function, thereby possibly contributing to tumorigenesis.

Received for publication, January 3, 2005 , and in revised form, February 23, 2005.

^* This work was supported by funding from the National Medical Research Council of Singapore (NMRC) and Biomedical Research Council of Singapore (BMRC) (to K. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, National Cancer Centre, 11, Hospital Dr., Singapore 169610, Singapore. Tel.: 65-6436-8349; Fax: 65-6226-5694; E-mail: cmrksb{at}nccs.com.sg.

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