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Sigma-1 receptors regulate Bcl-2 expression by reactive oxygen species-dependent transcriptional regulation of

Johann Meunier1, Teruo Hayashi

  • 1Cellular Pathobiology Section, Cellular Neurobiology Research Branch, IRP, NIDA, National Institutes of Health, DHHS, Triad Technology Building, Baltimore, MD, USA.

The Journal of Pharmacology and Experimental Therapeutics
|October 27, 2009
PubMed

Insights

The sigma-1 receptor (Sig-1R) promotes cell survival by regulating Bcl-2 expression. This occurs via the reactive oxygen species (ROS)/nuclear factor kappaB (NF-kappaB) pathway, influencing Bcl-2 transcription.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Bcl-2 is a key antiapoptotic protein.
  • Reactive oxygen species (ROS) influence Bcl-2 expression.
  • The sigma-1 receptor (Sig-1R) is a chaperone with protective functions, but its antiapoptotic mechanisms are unclear.

Purpose of the Study:

  • To elucidate the mechanisms by which Sig-1R exerts its antiapoptotic action.
  • To investigate the role of Sig-1R in regulating Bcl-2 expression.
  • To determine the involvement of ROS and NF-kappaB in Sig-1R-mediated cell survival.

Main Methods:

  • Investigated Sig-1R and Bcl-2 expression in Chinese hamster ovary cells.
  • Utilized siRNA for Sig-1R knockdown and overexpression.
  • Employed ROS scavengers and NF-kappaB inhibitors (e.g., oridonin).
  • Analyzed protein levels of NF-kappaB precursors and inhibitors.
  • Assessed apoptosis induction by H(2)O(2).

Main Results:

  • Sig-1R regulates Bcl-2 expression transcriptionally, not via protein stability or direct association.
  • Sig-1R knockdown decreased Bcl-2 expression, while overexpression increased it.
  • The effect of Sig-1R knockdown on Bcl-2 was mitigated by ROS scavengers and NF-kappaB inhibition.
  • Sig-1R knockdown affected NF-kappaB pathway components (p105, IkappaBalpha, p50).
  • Sig-1R knockdown enhanced H(2)O(2)-induced apoptosis, which was blocked by NF-kappaB inhibition or Bcl-2 overexpression.

Conclusions:

  • Sig-1R promotes cell survival by transcriptionally upregulating Bcl-2 expression.
  • This regulation is mediated through the ROS/NF-kappaB signaling pathway.
  • Sig-1R plays a crucial role in cellular protection against apoptosis via Bcl-2 modulation.

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