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J. Biol. Chem., Vol. 279, Issue 49, 50976-50985, December 3, 2004

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p53-dependent Down-regulation of Telomerase Is Mediated by p21^waf1*

Igor Shats, Michael Milyavsky, Xiaohu Tang, Perry Stambolsky, Neta Erez, Ran Brosh, Ira Kogan, Ilana Braunstein, Maty Tzukerman, Doron Ginsberg, and Varda Rotter¶

From the Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel and the Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel

Inactivation of p53 and activation of telomerase occur in the majority of human cancers, raising the possibility of a link between these two pathways. Overexpression of wild-type p53 down-regulates the enzymatic activity of telomerase in various cancer cell lines through transcriptional repression of its catalytic subunit, human telomerase reverse transcriptase (hTERT). In this study, we re-evaluated the role of p53 in telomerase regulation using isogenic cell lines expressing physiological levels of p53. We demonstrate that endogenous wild-type p53 was able to down-regulate telomerase activity, hTERT mRNA levels, and promoter activity; however, the ability to repress hTERT expression was found to be cell type-specific. The integrity of the DNA-binding core domain, the N-terminal transactivation domain, and the C-terminal oligomerization domains of p53 was essential for hTERT promoter repression, whereas the proline-rich domain and the extreme C terminus were not required. Southwestern and chromatin immunoprecipitation experiments demonstrated lack of p53 binding to the hTERT promoter, raising the possibility of an indirect repressive mechanism. The down-regulation of hTERT promoter activity was abolished by a dominant-negative E2F1 mutant. Mutational analysis identified a specific E2F site responsible for p53-mediated repression. Knockdown of the key p53 transcriptional target, p21, was sufficient to eliminate the p53-dependent repression of hTERT. Inactivation of the Rb family using either viral oncoproteins or RNA interference attenuated the repression. Inhibition of histone deacetylases also interfered with the repression of hTERT by p53. Therefore, our results suggest that repression of hTERT by endogenous p53 is mediated by p21 and E2F.

Received for publication, March 5, 2004 , and in revised form, September 7, 2004.

^* This work was supported in part by grants from the Israel-United States of America Binational Science Foundation and the German Israeli Foundation for Scientific Research and Development. 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.

^¶ Incumbent of the Norman and Helen Asher Professorial Chair in Cancer Research at the Weizmann Institute. To whom correspondence should be addressed: Dept. of Molecular Cell Biology, Weizmann Inst. of Science, Herzl 1, Rehovot 76100, Israel. Tel.: 972-8-934-4501/946-6264; Fax: 972-8-946-5265; E-mail: varda.rotter{at}weizmann.ac.il.

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