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J. Biol. Chem., Vol. 281, Issue 8, 4557-4563, February 24, 2006

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The RASSF1A Tumor Suppressor Activates Bax via MOAP-1^*

Michele D. Vos, Ashraf Dallol, Kristin Eckfeld, Nadia P. C. Allen, Howard Donninger, Luke B. Hesson, Diego Calvisi^¶, Farida Latif¹, and Geoffrey J. Clark²

From the Department of Cell and Cancer Biology, NCI, National Institutes of Health, Rockville, Maryland 20850-3300, the ^¶Department of Biomedical Sciences, University of Sassari, 07110 Sassari, Italy, and the Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, University of Birmingham, Birmingham B15 2TT, United Kingdom

The novel tumor suppressor RASSF1A is frequently inactivated during human tumorigenesis by promoter methylation. RASSF1A may serve as a node in the integration of signaling pathways controlling a range of critical cellular functions including cell cycle, genomic instability, and apoptosis. The mechanism of action of RASSF1A remains under investigation. We now identify a novel pathway connecting RASSF1A to Bax via the Bax binding protein MOAP-1. RASSF1A and MOAP-1 interact directly, and this interaction is enhanced by the presence of activated K-Ras. RASSF1A can activate Bax via MOAP-1. Moreover, activated K-Ras, RASSF1A, and MOAP-1 synergize to induce Bax activation and cell death. Analysis of a tumor-derived point mutant of RASSF1A showed that the mutant was defective for the MOAP-1 interaction and for Bax activation. Moreover, inhibition of RASSF1A by shRNA impaired the ability of K-Ras to activate Bax. Thus, we identify a novel pro-apoptotic pathway linking K-Ras, RASSF1A and Bax that is specifically impaired in some human tumors.

Received for publication, November 10, 2005

^* 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 Supported in part by the Association for International Cancer Research.

² To whom correspondence should be addressed: Dept. of Cell and Cancer Biology, NCI, 9610 Medical Center Dr., Rockville, MD 20850-3300. Tel.: 301-594-7288; Fax: 301-402-4422; E-mail: gclark{at}mail.nih.gov.

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