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J. Biol. Chem., Vol. 282, Issue 22, 16223-16231, June 1, 2007

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Functional Linkage between NOXA and Bim in Mitochondrial Apoptotic Events^*

Jie Han¹, Leslie A. Goldstein¹, Wen Hou, and Hannah Rabinowich²

From the Department of Pathology, University of Pittsburgh School of Medicine, and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213

NOXA is a BH3-only protein whose expression is induced by certain p53-depenent or independent apoptotic stimuli. Both NOXA and Bim are avid binders of Mcl-1, but a functional linkage between these BH3-only proteins has not yet been reported. In this study, we demonstrate that Mcl-1 binding of endogenously induced NOXA interferes with the ability of Mcl-1 to efficiently sequester endogenous Bim, as Bim is displaced from its complex with Mcl-1. Induced NOXA significantly enhances the UV sensitivity of cells, and the ensuing mitochondrial depolarization is entirely abrogated by Bim knockdown. These results demonstrate a Mcl-1-mediated cross-talk between endogenous NOXA and Bim that occurs upstream of the Bak/Bax-dependent execution of UV-induced mitochondrial depolarization. The current findings demonstrate that the mitochondrial response to an induced expression of NOXA is executed by endogenous Bim and suggest a plausible mechanism for the observed NOXA-Bim linkage.

Received for publication, December 6, 2006 , and in revised form, March 13, 2007.

^* This work was supported by National Institutes of Health Grants RO1 CA109285 and RO1 CA111786 and by Department of Defense Grant DAMD17-02-1-0552 (to H. R.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: University of Pittsburgh Cancer Institute, The Hillman Cancer Center, Research Pavilion, Rm. G17c, 5117 Centre Ave., Pittsburgh, PA 15213. Tel.: 412-623-3212; Fax: 412-623-1119; E-mail: rabinow{at}pitt.edu.

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