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Molecular and Cellular Biology, November 2005, p. 9369-9382, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9369-9382.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Loss of Bif-1 Suppresses Bax/Bak Conformational Change and Mitochondrial Apoptosis

Yoshinori Takahashi,1 Mariusz Karbowski,3 Hirohito Yamaguchi,1 Aslamuzzaman Kazi,1 Jie Wu,2 Saïd M. Sebti,1 Richard J. Youle,3 and Hong-Gang Wang1*

Drug Discovery Program,1 Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612,2 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 208923

Received 3 May 2005/ Returned for modification 7 June 2005/ Accepted 2 August 2005

Bif-1, a member of the endophilin B protein family, interacts with Bax and promotes interleukin-3 withdrawal-induced Bax conformational change and apoptosis when overexpressed in FL5.12 cells. Here, we provide evidence that Bif-1 plays a regulatory role in apoptotic activation of not only Bax but also Bak and appears to be involved in suppression of tumorigenesis. Inhibition of endogenous Bif-1 expression in HeLa cells by RNA interference abrogated the conformational change of Bax and Bak, cytochrome c release, and caspase 3 activation induced by various intrinsic death signals. Similar results were obtained in Bif-1 knockout mouse embryonic fibroblasts. While Bif-1 did not directly interact with Bak, it heterodimerized with Bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the Bax conformational change. Moreover, suppression of Bif-1 expression was associated with an enhanced ability of HeLa cells to form colonies in soft agar and tumors in nude mice. Taken together, these findings support the notion that Bif-1 is an important component of the mitochondrial pathway for apoptosis as a novel Bax/Bak activator, and loss of this proapoptotic molecule may contribute to tumorigenesis.

* Corresponding author. Mailing address: Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Phone: (813) 979-6764. Fax: (813) 979-7265. E-mail: wanghg{at}moffitt.usf.edu.

Molecular and Cellular Biology, November 2005, p. 9369-9382, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9369-9382.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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