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J. Biol. Chem., Vol. 281, Issue 35, 25588-25600, September 1, 2006

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Transforming Growth Factor Suppresses Human Telomerase Reverse Transcriptase (hTERT) by Smad3 Interactions with c-Myc and the hTERT Gene^*

He Li¹, Dakang Xu¹, Jinhua Li¹², Michael C. Berndt, and Jun-Ping Liu³

From the Department of Immunology and Monash Institute of Medical Research, Monash University, Melbourne, Victoria 3181, Australia

Telomerase underpins stem cell renewal and proliferation and is required for most neoplasia. Recent studies suggest that hormones and growth factors play physiological roles in regulating telomerase activity. In this report we show a rapid repression of the telomerase reverse transcriptase (TERT) gene by transforming growth factor (TGF-) in normal and neoplastic cells by a mechanism depending on the intracellular signaling protein Smad3. In human breast cancer cells TGF- induces rapid entry of Smad3 into the nucleus where it binds to the TERT gene promoter and represses TERT gene transcription. Silencing Smad3 gene expression or genetically deleting the Smad3 gene disrupts TGF- repression of TERT gene expression. Expression of the Smad3 antagonist, Smad7, also interrupts TGF--mediated Smad3-induced repression of the TERT gene. Mutational analysis identified the Smad3 site on the TERT gene promoter, mediating TERT repression. In response to TGF-, Smad3 binds to c-Myc; knocking down c-Myc, Smad3 does not bind to the TERT gene, suggesting that c-Myc recruits Smad3 to the TERT promoter. Thus, TGF- negatively regulates telomerase activity via Smad3 interactions with c-Myc and the TERT gene promoter. Modifying the interaction between Smad3 and TERT gene may, thus, lead to novel strategies to regulate telomerase.

Received for publication, March 14, 2006 , and in revised form, June 19, 2006.

^* This work was supported by grants from the Australia Research Council and National Health and Medical Research Council of Australia. 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.

¹ These authors contributed equally to this work.

² Current address: Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria 3800, Australia.

³ To whom correspondence should be addressed: Dept. of Immunology, AMREP, Monash Medical School, Commercial Road, Prahran, Victoria 3181, Australia. Tel.: 61-3-99030715; Fax: 61-3-99030120; E-mail: jun-ping.liu{at}med.monash.edu.au.

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