Meunier J, Hayashi T
Sigma-1 receptors regulate Bcl-2 expression by ROS-dependent transcriptional regulation of NF-{kappa}B. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Oct 23.
The expression of Bcl-2, the major anti-apoptotic member of the Bcl-2 family, is under complex controls of several factors including reactive oxygen species (ROS). The sigma-1 receptor (Sig-1R), which was recently identified as a novel molecular chaperone at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), has been shown to exert robust cellular protective actions. However, mechanisms underlying the antiapoptotic action of the Sig-1R remain to be clarified. Here, we found that the Sig-1R promotes cellular survival by regulating the Bcl-2 expression in CHO cells. Though both Sig-1Rs and Bcl-2 are highly enriched at the MAM, Sig-1Rs neither associate physically with Bcl-2 nor regulate stability of Bcl-2 proteins. However, Sig-1Rs tonically regulate the expression of Bcl-2 proteins. Knockdown of Sig-1Rs downregulates, whereas overexpression of Sig-1Rs upregulates bcl-2 mRNA, indicating that the Sig-1R transcriptionally regulates the expression of Bcl-2. Importantly, the effect of Sig-1R siRNA downregulating Bcl-2 was blocked by ROS scavengers as well as by the inhibitor of the ROS-inducible transcription factor NF-kappaB. Knockdown of Sig-1Rs upregulates p105, the precursor of NF-kappaB, while concomitantly decreases IkappaBalpha. Sig-1R knockdown also accelerates the conversion of p105 to the active form p50. Lastly, we demonstrated that knockdown of Sig-1Rs potentiates H(2)O(2)-induced apoptosis; the action is blocked by either the NF-kappaB inhibitor oridonin or overexpression of Bcl-2. These findings thus suggest that Sig-1Rs promote cell survival, at least in part, by transcriptionally regulating Bcl-2 expression via the ROS-NF-kappaB pathway.
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