Activation of NF‐κB by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers

FEBS Letters

Pahl, Heike L.²  Baeuerle, Patrick A.¹ 

[1] Tularik, Inc., Two Corporate Drive, South San Francisco, CA 94080, USA;Institute for Experimental Cancer Research, Tumor Biology Center, P.O. Box 1120, D-79104 Freiburg, Germany

关键词: Endoplasmic reticulum;    NF-κB;    Ca2+;    Radical oxygen intermediate;   

DOI  :  10.1016/0014-5793(96)00800-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The eukaryotic transcription factor NF-κB 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-κB. Here, we show that activation of NF-κB 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-κB activation by various ER stress-eliciting agents, whereas only antioxidants but not the Ca²⁺ chelators prevented NF-κB activation by the inflammatory cytokine TNF-α. 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-κB. 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-κB 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.

【 授权许可】

Unknown