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Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B

Angel G Martin1, Jason Trama, Diane Crighton

  • 1Apoptosis Section, NCI-Frederick, Frederick, MD 21702, USA. agmartin@inbiomed.org

Aging
|March 3, 2010
PubMed

Insights

The transcription factor NF-kappaB is crucial for genotoxin-induced apoptosis by enabling Noxa expression. Loss of NF-kappaB impairs cytochrome c release and cell death pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Nuclear factor-kappa B (NF-kappaB) is known to inhibit extrinsic apoptosis but its role in p53-induced apoptosis is unclear.
  • Understanding NF-kappaB's function in apoptosis is critical for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the mechanism by which NF-kappaB regulates p53-induced apoptosis.
  • To investigate the role of NF-kappaB in genotoxin-induced apoptosis in transformed cells.

Main Methods:

  • Utilized p65-null mouse embryonic fibroblasts (MEFs) to study NF-kappaB-deficient cells.
  • Performed gene profiling via microarray analysis to identify NF-kappaB-regulated genes.
  • Investigated the activation of p73 and its role in Noxa gene expression.

Main Results:

  • NF-kappaB deficiency compromised genotoxin-induced cytochrome c release in transformed MEFs.
  • NF-kappaB is essential for the expression of Noxa, a pro-apoptotic BH3-only protein.
  • Genotoxin treatment failed to induce Noxa mRNA expression in the absence of NF-kappaB.
  • p73 activation following genotoxin treatment requires NF-kappaB, and p73 induces Noxa expression.

Conclusions:

  • NF-kappaB is indispensable for genotoxin-induced apoptosis by regulating Noxa expression.
  • The NF-kappaB/p73 pathway is critical for activating Noxa and initiating apoptosis in response to DNA damage.
  • Loss of NF-kappaB function abrogates genotoxin-induced apoptosis, offering insights into cancer development and treatment.
Keywords:
NF-κB BNoxaapoptosisp73

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