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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
07:42

Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c

Published on: June 29, 2011

c-Myc sensitizes cells to tumor necrosis factor-mediated apoptosis by inhibiting nuclear factor kappa B

Zongbing You1, Lee V Madrid, Daniel Saims

  • 1Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.

The Journal of Biological Chemistry
|August 1, 2002
PubMed

Insights

The oncogene c-Myc inhibits nuclear factor kappaB (NF-kappaB) activation, promoting tumor necrosis factor (TNF)-induced apoptosis by blocking survival genes like A1. This clarifies how c-Myc sensitizes cells to cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Nuclear factor kappaB (NF-kappaB) is crucial in preventing tumor necrosis factor (TNF)-mediated apoptosis by upregulating anti-apoptotic genes.
  • c-Myc expression can sensitize cells to TNF-induced apoptosis, but its precise inhibitory mechanism on NF-kappaB signaling remains unclear.

Purpose of the Study:

  • To elucidate the specific molecular mechanisms by which c-Myc influences NF-kappaB signaling and sensitizes cells to TNF-mediated apoptosis.
  • To identify the precise step in the NF-kappaB pathway affected by c-Myc.

Main Methods:

  • Utilized an inducible c-MycER system and c-Myc null fibroblasts.
  • Investigated the effects of c-Myc expression on NF-kappaB activation, nuclear translocation, and transactivation.
  • Assessed cytochrome c release and the expression of NF-kappaB-inducible gene A1.

Main Results:

  • c-Myc expression inhibited NF-kappaB activation by interfering with RelA/p65 transactivation, not nuclear translocation.
  • c-Myc promoted TNF-induced cytochrome c release from mitochondria due to NF-kappaB inhibition.
  • c-Myc attenuated the expression of the NF-kappaB-inducible gene A1, and restoring A1 expression reduced c-Myc-induced sensitization to TNF.

Conclusions:

  • c-Myc increases cell susceptibility to TNF-mediated apoptosis by inhibiting NF-kappaB activation and repressing the expression of survival genes like A1.
  • These findings reveal a molecular mechanism for c-Myc's pro-apoptotic activity in the context of TNF signaling.

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