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INrf2 (Keap1) targets Bcl-2 degradation and controls cellular apoptosis

S K Niture1, A K Jaiswal

  • 1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Cell Death and Differentiation
|September 25, 2010
PubMed

Insights

Cytosolic inhibitor of Nrf2 (INrf2) degrades the antiapoptotic Bcl-2 protein, controlling cellular apoptosis. Dysfunctional INrf2 in cancer cells impairs this process, impacting drug resistance and survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • NF-E2-related factor 2 (Nrf2) is a master regulator of cytoprotective genes.
  • Cytosolic inhibitor of Nrf2 (INrf2) targets Nrf2 for degradation.
  • The role of INrf2 in regulating apoptosis is not well understood.

Purpose of the Study:

  • To investigate the role of INrf2 in the regulation of cellular apoptosis.
  • To elucidate the molecular mechanism by which INrf2 controls apoptosis.
  • To explore the implications of INrf2-mediated apoptosis in cancer.

Main Methods:

  • Co-immunoprecipitation assays to study protein interactions.
  • Western blotting to assess protein levels.
  • Caspase activity assays and DNA fragmentation analysis to measure apoptosis.
  • In vitro ubiquitination assays.

Main Results:

  • INrf2 directly interacts with and ubiquitinates the antiapoptotic protein Bcl-2, leading to its degradation.
  • INrf2 promotes etoposide-induced apoptosis by increasing Bax, cytochrome c release, and caspase activation.
  • Antioxidants disrupt the INrf2-Bcl-2 interaction, stabilizing Bcl-2 and reducing apoptosis.
  • Mutant INrf2 in lung cancer cells fails to degrade Bcl-2, conferring resistance to DNA-damaging agents.

Conclusions:

  • INrf2 is a novel regulator of Bcl-2 stability and cellular apoptosis.
  • The INrf2-Bcl-2 axis is a potential therapeutic target for cancer treatment.
  • Dysfunctional INrf2 contributes to cancer cell survival and drug resistance.

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