c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway

J Biol Chem. 2002 Nov 8;277(45):43224-32. doi: 10.1074/jbc.M206967200. Epub 2002 Aug 28.


Activation of c-Myc sensitizes cells to apoptosis induction by ligand-activated death receptors. Such sensitization to death receptors by oncogenes may well be the mechanism underlying tumor cell sensitivity to tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL). The mechanism by which this c-Myc-induced sensitization occurs is unclear but could involve modulation of expression of death receptors or their ligands or potentiation of the sensitivity of mitochondria to release pro-apoptotic effectors such as holocytochrome c. Here, we show that ectopic expression of the death receptor signaling protein RIP (receptor-interactive protein) triggers apoptosis via a FAS-associated death domain protein (FADD) and caspase 8-dependent pathway. Induction of apoptosis by this intracellular activation of the death receptor signaling pathway is significantly augmented by c-Myc expression. Moreover, c-Myc expression strongly promotes the potential of RIP to induce cytochrome c release from mitochondria. This implicates the mitochondrial apoptotic pathway in this synergy, a notion confirmed by the inability of c-Myc to sensitize to RIP killing in cells lacking the obligate mitochondrial apoptotic effectors Bax and Bak. We conclude that the lethality of the RIP-activated cytosolic caspase 8 pathway is augmented by c-Myc priming mitochondria to release cytochrome c. This places the intersection of apoptotic synergy between c-Myc and death receptor signaling downstream of the death receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis / physiology*
  • Carrier Proteins / metabolism
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Cell Death
  • Cell Line
  • Fas-Associated Death Domain Protein
  • Gene Transfer Techniques
  • Mitochondria / physiology*
  • Models, Biological
  • Mutagenesis
  • Proteins / physiology*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Rats
  • Recombinant Proteins / metabolism
  • Sequence Deletion
  • Signal Transduction / physiology*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Fadd protein, rat
  • Fas-Associated Death Domain Protein
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • Recombinant Proteins
  • Casp8 protein, rat
  • Casp9 protein, rat
  • Caspase 8
  • Caspase 9
  • Caspases