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J. Biol. Chem., Vol. 282, Issue 48, 35293-35307, November 30, 2007

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NM23-H1 Tumor Suppressor and Its Interacting Partner STRAP Activate p53 Function^*

From the Department of Biochemistry, Biotechnology Research Institute, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea

p53 plays a critical role in a variety of growth inhibitory responses, including cell cycle arrest, differentiation, and apoptosis, and contributes to tumor suppression. Here we show that NM23-H1 and its binding partner STRAP (serine-threonine kinase receptor-associated protein) interact with p53 and potentiate p53 activity. Both NM23-H1 and STRAP directly interact with the central DNA binding domain within residues 113-290. The use of NM23-H1 and STRAP mutants revealed that Cys¹⁴⁵ of NM23-H1 and Cys¹⁵² (or Cys²⁷⁰) of STRAP were responsible for p53 binding. Furthermore, Cys¹⁷⁶ and Cys¹³⁵ of p53 were required to bind NM23-H1 and STRAP, respectively. Ectopic expression of wild-type NM23-H1 and STRAP, but not NM23-H1(C145S) and STRAP(C152S/C270S), positively regulated p53-mediated transcription in a dose-dependent manner. Knockdown of endogenous NM23-H1 or STRAP produced an opposite trend and inhibited the p53-mediated transcription. Similarly, NM23-H1 and STRAP stimulated p53-induced apoptosis and growth inhibition, whereas the NM23-H1(C145S) and STRAP(C152S/C270S) mutants had no effect. We also demonstrated that p53 activation by NM23-H1 and STRAP was mediated by removing Mdm2, a negative regulator of p53, from the p53-Mdm2 complex. These results suggest that NM23-H1 and its interacting partner STRAP physically interact with p53 and positively regulate its functions, including p53-induced apoptosis and cell cycle arrest.

Received for publication, June 25, 2007 , and in revised form, August 31, 2007.

^* This work was supported by grants from the National Research and Development Program for Cancer Control, Ministry of Health & Welfare Grant 0620090-1, the Korean Health 21 Research and Development Project, Ministry of Health & Welfare Grant A060378, Chungbuk National University Grant 2006, and in part by Korea Science and Engineering Foundation Grant R0A-2007-000-20006-0 funded by the Korea Government (Ministry of Science and Technology). 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 To whom correspondence should be addressed: Dept. of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 361-763, Republic of Korea. Tel.: 82-43-261-3233; Fax: 82-43-267-2306; E-mail: hyunha{at}chungbuk.ac.kr.

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