Functional Linkage between NOXA and Bim in Mitochondrial Apoptotic Events*
- ‡Department of Pathology, University of Pittsburgh School of Medicine, and the §University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213
- ↵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.
Abstract
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 December 6, 2006.
- Revision received March 13, 2007.
- The American Society for Biochemistry and Molecular Biology, Inc.
