title: 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.
authors.affiliation: University of California at San Francisco Cancer Center, San Francisco, California 94143-0128, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Juin
authors.forename: Abigail
authors.initials: A
authors.lastname: Hunt
authors.forename: Trevor
authors.initials: T
authors.lastname: Littlewood
authors.forename: Beatrice
authors.initials: B
authors.lastname: Griffiths
authors.forename: Lamorna Brown
authors.initials: LB
authors.lastname: Swigart
authors.forename: Stanley
authors.initials: S
authors.lastname: Korsmeyer
authors.forename: Gerard
authors.initials: G
authors.lastname: Evan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D003574:Cytochrome c Group / Q000032:analysis; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology; D016259:Genes, myc; D016158:Genes, p53; D005816:Genetic Complementation Test; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008845:Microinjections; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013329:Structure-Activity Relationship; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494773:Bak1 protein, mouse; C494774:Bak1 protein, rat; C494827:Bax protein, mouse; C494828:Bax protein, rat; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D003574:Cytochrome c Group; D008565:Membrane Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein