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.
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis / genetics
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Apoptosis / physiology*
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Cell Line
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Cytochrome c Group / analysis
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Embryo, Mammalian
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Fibroblasts / cytology
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Genes, myc
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Genes, p53
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Genetic Complementation Test
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / physiology
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Mice
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Mice, Knockout
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Microinjections
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Mitochondria / enzymology
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Molecular Sequence Data
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Peptide Fragments / pharmacology
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Promoter Regions, Genetic
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Protein Conformation
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-myc / physiology*
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Rats
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Recombinant Fusion Proteins / physiology
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Structure-Activity Relationship
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Transfection
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / physiology
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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bcl-X Protein
Substances
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Bak1 protein, mouse
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Bak1 protein, rat
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Bax protein, mouse
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Bax protein, rat
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Bcl2l1 protein, mouse
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Bcl2l1 protein, rat
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Cytochrome c Group
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Membrane Proteins
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Peptide Fragments
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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Recombinant Fusion Proteins
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Tumor Suppressor Protein p53
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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bcl-X Protein