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J. Biol. Chem., Vol. 280, Issue 10, 9745-9751, March 11, 2005

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Molecular Mechanism of Inhibition of Survivin Transcription by the GC-rich Sequence-selective DNA Binding Antitumor Agent, Hedamycin

EVIDENCE OF SURVIVIN DOWN-REGULATION ASSOCIATED WITH DRUG SENSITIVITY^*

Jianguo Wu, Xiang Ling, Dalin Pan, Pasha Apontes, Lei Song, Ping Liang, Dario C. Altieri¶, Terry Beerman, and Fengzhi Li||

From the Departments of Pharmacology and Therapeutics and Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 and the ^¶Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Expression of the antiapoptotic protein survivin is associated with cancer cell viability and drug resistance. Thus, control of its expression in cancer cells has significant consequences for cancer therapeutics. Here we have shown that hedamycin, a GC-rich DNA binding drug, down-regulated survivin expression. Using a series of survivin promoter-luciferase constructs, we have identified an 86-bp GC-rich DNA element (-124 to -39) that mediates the ability of hedamycin to down-regulate survivin expression. Furthermore, both in vivo foot-printing and in vitro gel mobility shift experiments revealed that hedamycin bound to a 21-bp GC-rich DNA element (-115 to -95) in the survivin promoter. This drug-DNA interaction abrogated the binding of Sp-1 or Sp1-like proteins to the 21-bp cis-acting DNA element, and mutagenesis of this region consistently diminished survivin promoter activity. Finally, down-regulation of survivin transcription by hedamycin modulated the viability of cancer cells. These data suggest that abrogation of Sp-1 or Sp1-like protein binding to the 21-bp DNA element in the survivin promoter contributes at least in part to the inhibitory effect of hedamycin on survivin gene transcription. Drug-induced modulation of survivin gene expression may provide novel approaches for cancer therapeutics.

Received for publication, August 16, 2004 , and in revised form, December 21, 2004.

^* This study was sponsored in part by grants from Concern Foundation (Beverly Hills, CA) and Elsa U. Pardee Foundation (Midland, MI) (to F. L.) and National Institutes of Health Grants CA101515 (to P. L.), CA78810 and CA90917 (to D. C. A.), CA080939 (to T. B.), and CA109481 to (F. L.). 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: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Inst., Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-4398; Fax: 716-845-8857; E-mail: fengzhi.li{at}roswellpark.org.

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