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Molecular and Cellular Biology, September 2002, p. 6158-6169, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6158-6169.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

c-Myc Functionally Cooperates with Bax To Induce Apoptosis

Philippe Juin,1,2 Abigail Hunt,1 Trevor Littlewood,3 Beatrice Griffiths,1 Lamorna Brown Swigart,1 Stanley Korsmeyer,4 and Gerard Evan1*

University of California at San Francisco Cancer Center, San Francisco, California 94143-0128,1 Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115,4 INSERM U419, 44035 Nantes Cedex 035, France,2 Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom3

Received 14 January 2002/ Returned for modification 14 March 2002/ Accepted 11 June 2002

c-Myc promotes apoptosis by destabilizing mitochondrial integrity, leading to the release of proapoptotic effectors including holocytochrome c. Candidate mediators of c-Myc in this process are the proapoptotic members of the Bcl-2 family. We show here that fibroblasts lacking Bak remain susceptible to c-Myc-induced apoptosis whereas bax-deficient fibroblasts are resistant. However, despite this requirement for Bax, c-Myc activation exerts no detectable effects on Bax expression, localization, or conformation. Moreover, susceptibility to c-Myc-induced apoptosis can be restored in bax-deficient cells by ectopic expression of Bax or by microinjection of a peptide comprising a minimal BH3 domain. Microinjection of BH3 peptide also restores sensitivity to c-Myc-induced apoptosis in p53-deficient primary fibroblasts that are otherwise resistant. By contrast, there is no synergy between BH3 peptide and c-Myc in fibroblasts deficient in both Bax and Bak. We conclude that c-Myc triggers a proapoptotic mitochondrial destabilizing activity that cooperates with proapoptotic members of the Bcl-2 family.

* Corresponding author. Mailing address: UCSF Cancer Center, 2340 Sutter St., San Francisco, CA 94143-0128. Phone: (415) 514-0438. Fax: (415) 514-0878. E-mail: gevan{at}cc.ucsf.edu.

Molecular and Cellular Biology, September 2002, p. 6158-6169, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6158-6169.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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