c-Myc Functionally Cooperates with Bax To Induce Apoptosis

Abstract

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.

We thank Craig Thompson for the gift of Bak-deficient mice and the bax^−/− /bak^−/− MEFs, Larry Donehower for the gift of p53-deficient mice, and Emmy Verschuren for the pcDNA3c-Myc plasmid. We thank Scott Lowe for the gift of p53^−/− /bax^−/− MEFs and for fruitful discussion throughout this work and Oliver von Ahsen, Ingram Iaccarino, Douglas Green, and François Vallette for invaluable comments. We also thank all members of the Evan lab for their constant support. We are particularly indebted to Dave Hancock for his help and criticism throughout this study.