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J. Biol. Chem., Vol. 281, Issue 13, 8600-8606, March 31, 2006

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WT p53, but Not Tumor-derived Mutants, Bind to Bcl2 via the DNA Binding Domain and Induce Mitochondrial Permeabilization^*

York Tomita, Natasha Marchenko, Susan Erster, Alice Nemajerova, Alexander Dehner^¶, Christian Klein^||, Hongguang Pan, Horst Kessler^¶, Petr Pancoska, and Ute M. Moll¹

From the Department of Pathology, Stony Brook University, Stony Brook, New York 11794-8691, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C. 20057, ^||Pharma Research, Roche Diagnostics GmbH, D-82372 Penzberg, Germany, and ^¶Institut für Organische Chemie und Biochemie, Technische Universität München, D-85747 Garching, Germany

The induction of apoptosis by p53 in response to cellular stress is its most conserved function and crucial for p53 tumor suppression. We recently reported that p53 directly induces oligomerization of the BH1,2,3 effector protein Bak, leading to outer mitochondrial membrane permeabilization (OMMP) with release of apoptotic activator proteins. One important mechanism by which p53 achieves OMMP is by forming an inhibitory complex with the anti-apoptotic BclXL protein. In contrast, the p53 complex with the Bcl2 homolog has not been interrogated. Here we have undertaken a detailed characterization of the p53-Bcl2 interaction using structural, biophysical, and mutational analyses. We have identified the p53 DNA binding domain as the binding interface for Bcl2 using solution NMR. The affinity of the p53-Bcl2 complex was determined by surface plasmon resonance analysis (BIAcore) to have a dominant component K_D 535 ± 24 nM. Moreover, in contrast to wild type p53, endogenous missense mutants of p53 are unable to form complexes with endogenous Bcl2 in human cancer cells. Functionally, these mutants are all completely or strongly compromised in mediating OMMP, as measured by cytochrome c release from isolated mitochondria. These data implicate p53-Bcl2 complexes in contributing to the direct mitochondrial p53 pathway of apoptosis and further support the notion that the DNA binding domain of p53 is a dual function domain, mediating both its transactivation function and its direct mitochondrial apoptotic function.

Received for publication, July 13, 2005 , and in revised form, December 22, 2005.

^* This work was supported by National Institutes of Health Grant CA060664 and by Philip Morris USA and Philip Morris International (to U. M. M.). 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. Tel.: 631-444-2459; Fax: 631-444-3424; E-mail: umoll{at}notes.cc.sunysb.edu.

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