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Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1's inhibitory effect on Bak

Oncogene volume 31, pages 3177–3189 (2012)Cite this article

Abstract

The intrinsic mitochondrial apoptotic pathway acts through two core pro-apoptotic proteins Bax (Bcl2-associated X protein) and Bak (Bcl2-antagonist/killer 1). Although Bax and Bak seem to have redundant roles in apoptosis, accumulating evidence also suggests that they might not be interchangeable under certain conditions, at least in some human cell lines. Here we report the generation of Bak knockout as well as BaxBak double knockout HCT116 human colon carcinoma cells. We show that Bak is dispensable for apoptosis induced by a variety of stimuli including ABT-737 but not for fluorouracil-induced apoptosis. In addition, Bax deficiency only provides partial protection against camptothecin and cisplatin-induced apoptosis and no protection against killing by Puma or ABT-737 plus Noxa overexpression. Moreover, Bak is activated normally in response to many chemotherapeutic drugs in the presence of Bax, but remains kept in check by Mcl-1 in the absence of Bax. Our data suggest that Bax and Bak are functionally redundant, but they are counteracted by distinct anti-apoptotic Bcl-2 family proteins in different species.

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Acknowledgements

We thank Bert Vogelstein for Bax KO HCT116 cells, Fred Bunz for pSEPT vector and advice on gene targeting, Jean-Claude Martinou for comments on the manuscript, NINDS DNA sequencing facility, NINDS imaging facility and NINDS FACS facility. This study is supported in part by the Intramural Research Program of the National Institutes of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH).

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  1. Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    C Wang & R J Youle

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Correspondence to R J Youle.

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Wang, C., Youle, R. Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1's inhibitory effect on Bak. Oncogene 31, 3177–3189 (2012). https://doi.org/10.1038/onc.2011.497

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