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J. Biol. Chem., Vol. 279, Issue 15, 14649-14655, April 9, 2004

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Direct Activation of HSP90A Transcription by c-Myc Contributes to c-Myc-induced Transformation^*

Shu-Chun Teng, Yung-Yi Chen¶, Yi-Ning Su||, Po-Chien Chou¶, Yu-Chi Chiang¶, Shun-Fu Tseng, and Kou-Juey Wu¶**

From the ^¶Institute of Biochemistry, National Yang-Ming University, Taipei 112, Taiwan and Graduate Institute of Microbiology, College of Medicine and ^||Department of Medical Genetics, National Taiwan University, Taipei 100, Taiwan

The c-myc proto-oncogene encodes a ubiquitous transcription factor involved in the control of cell growth and differentiation and implicated in inducing tumorigenesis. Understanding the function of c-Myc and its role in cancer depends upon the identification of c-Myc target genes. Heat shock protein 90 (HSP90) is involved in the folding of proteins such as signal transduction molecules (Src, Raf1, cdk4) and steroid receptors and in enhancing the activity of telomerase and nitric-oxide synthase. Here we show that c-Myc directly activates HSP90A transcription. c-Myc-mediated induction of HSP90A transcription occurs in different tissues, is independent of cell proliferation, and is mediated by a c-Myc binding site in the proximal promoter region of HSP90A gene. Overexpression of HSP90A in Rat1a cells induces transformation. Short interference RNA of HSP90A/Hsp86 reduces transformation activity in HeLa and RatMyc cells. These results indicate that by induction of HSP90A c-Myc may control the activity of multiple signal pathways involved in cellular transformation.

Received for publication, August 11, 2003 , and in revised form, January 5, 2004.

^* This work was supported in part by National Science Council Grants NSC 91-2320-B-002-070 and NSC 92-2320-B-010-078 (to K.-J. W.) and NSC 90-2311-B-002-073 (to S.-C. T.) and by National Health Research Institutes Grant NHRI-EX93-9329SI (to K.-J. W.). 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.

Contributed equally to the work.

^** To whom correspondence should be addressed. Tel.: 11886-228267328; Fax: 11886-228202449; E-mail: kjwu2{at}ym.edu.tw.

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