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FEBS Lett. 1996 Aug 26;392(2):129-36.

Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers.

Author information

1
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.

Abstract

The eukaryotic transcription factor NF-kappaB is activated by a large variety of stimuli. We have recently shown that ER stress, caused by an aberrant accumulation of membrane proteins within this organelle, also activates NF-kappaB. Here, we show that activation of NF-kappaB by ER stress requires an increase in the intracellular levels of both reactive oxygen intermediates (ROIs) and Ca2+. Two distinct intracellular Ca2+ chelators and a panel of structurally unrelated antioxidants prevented NF-kappaB activation by various ER stress-eliciting agents, whereas only antioxidants but not the Ca2+ chelators prevented NF-kappaB activation by the inflammatory cytokine TNF-alpha. Consistent with an involvement of calcium, the ER-resident Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid (CPA), which trigger a rapid efflux of Ca2+ from the ER, also potently activated NF-kappaB. Pretreatment with a Ca2+ chelator abrogated this induction. The Ca2+ chelator BAPTA-AM inhibited ROI formation in response to thapsigargin and CPA treatment, suggesting that the Ca2+ increase preceded ROI formation during NF-kappaB activation. The selective inhibitory effect of the drug tepoxalin suggests that the peroxidase activity of cyclooxygenases or lipoxygenases was responsible for the increased ROI production in response to Ca2+ release by thapsigargin.

PMID:
8772190
DOI:
10.1016/0014-5793(96)00800-9
[Indexed for MEDLINE]
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