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Gadd45a Expression Induces Bim Dissociation from the Cytoskeleton and Translocation to Mitochondria

Tong Tong,^1, Junfang Ji,^1, Shunqian Jin,^1,2 Xianxing Li,¹ Wenhong Fan,³ Yongmei Song,¹ Minrong Wang,¹ Zhihua Liu,¹ Min Wu,¹ and Qimin Zhan^1*

State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, People’s Republic of China,¹ Department of Radiation Oncology, Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213,² Department of Neurobiology, Institute of Basic Medical Sciences, Beijing 100850, People’s Republic of China³

Received 4 September 2004/ Returned for modification 22 February 2005/ Accepted 17 March 2005

Gadd45a, a p53- and BRCA1-regulated stress protein, has been implicated in the maintenance of genomic fidelity, probably through its roles in the control of cell cycle checkpoint and apoptosis. However, the mechanism(s) by which Gadd45a is involved in the induction of apoptosis remains unclear. We show here that inducible expression of Gadd45a protein causes dissociation of Bim, a Bcl2 family member, from microtubule-associated components and translocation to mitochondria. The Bim accumulation in mitochondria enhances interaction of Bim with Bcl-2, relieves Bax from Bcl-2-bound complexes, and subsequently results in release of cytochrome c into the cytoplasm. Suppression of endogenous Bim greatly inhibits Gadd45a induction of apoptosis. Interestingly, Gadd45a interacts with elongation factor 1 (EF-1), a microtubule-severing protein that plays an important role in maintaining cytoskeletal stability, and inhibits EF-1-mediated microtubule bundling, indicating that the interaction of Gadd45a with EF-1 disrupts cytoskeletal stability. A mutant form of Gadd45a harboring a deletion of EF-1-binding domain fails to inhibit microtubule stability and to induce Bim translocation to mitochondria. Furthermore, coexpression of EF-1 antagonizes Gadd45a's property of suppressing cell growth and inducing apoptosis. These findings identify a novel link that connects stress protein Gadd45a to the apoptotic machinery and address the importance of cytoskeletal stability in apoptotic response to DNA damage.

T.T. and J.J. contributed equally to this study.

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