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PMID: 16227588 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis.

Molecular and cellular biology ·Vol. 25 ·No. 21 ·2005-11-00 ·Pages 9369-82

Takahashi Y, Karbowski M, Yamaguchi H, Kazi A, Wu J, Sebti SM, Youle RJ, Wang HG

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics,metabolism Animals Apoptosis/physiology Caspases/metabolism Cells, Cultured Cytochromes c/metabolism Enzyme Activation Fibroblasts/physiology HeLa Cells Humans Mice Mice, Knockout Mitochondria/physiology Neoplasms, Experimental/genetics Protein Conformation RNA, Small Interfering/metabolism bcl-2 Homologous Antagonist-Killer Protein/metabolism bcl-2-Associated X Protein/metabolism
Chemicals
Adaptor Proteins, Signal Transducing BAK1 protein, human BAX protein, human Bak1 protein, mouse Bax protein, mouse RNA, Small Interfering SH3GLB1 protein, human Sh3glb1 protein, mouse bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein Cytochromes c Caspases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Takahashi Yoshinori
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Karbowski Mariusz
Yamaguchi Hirohito
Kazi Aslamuzzaman
Wu Jie
Sebti Saïd M
Youle Richard J
Wang Hong-Gang
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.21.9369-9382.2005
Published
2005-11-00
Pages
9369-82
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1265816
Subset
IM
Grants
NCI NIH HHS · R01 CA082197 · United States
NCI NIH HHS · CA 82197 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.21.9369-9382.2005 PMC Full Text View journal details
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