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MBC in Press, published online ahead of print March 12, 2008
Mol. Biol. Cell 10.1091/mbc.E07-11-1170

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Submitted on November 21, 2007
Revised on February 12, 2008
Accepted on February 29, 2008

Soft Substrate Upregulates the Interaction of STIM1 with Store-operated Ca2+ Channels that Lead to Normal Epithelial Cell Apoptosis

Wen-Tai Chiu,* Ming-Jer Tang,{dagger}{ddagger} Hsiao-Chun Jao,{sect} and Meng-Ru Shen{ddagger}{sect}||

*Institute of Basic Medical Sciences, {dagger}Department of Physiology, {ddagger}Center for Gene Regulation and Signal Transduction Research {sect}Department of Pharmacology, ||Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan

Monitoring Editor: Yu-Li Wang

We have demonstrated that soft substrate induced apoptosis in polarized cells, but not in transformed cells by disturbance of Ca2+ homeostasis. This study aims to further investigate the regulatory mechanisms underlying the disruption of Ca2+-signaling integrity in soft substrate-induced epithelial apoptosis. Soft substrate up-regulated the store-operated Ca2+ (SOC) entry across the plasma membrane of normal cervical epithelial cells, which resulted in increased cytosolic Ca2+ levels. Concomitantly, soft substrate induced the aggregation and translocation of stromal interacting molecule 1 (STIM1) toward the cell periphery to colocalize with Orai1, an essential pore subunit of SOC channel, detected by fluorescence resonance energy transfer approach and confocal image analyses. The disturbed Ca2+ homeostasis resulted in the activation of µ-calpain which cleaved {alpha}-spectrin, induced actin disorganization and caused apoptosis. In contrast, soft substrate did not disturb Ca2+ homeostasis or induce apoptosis in cervical cancer cells. Chelating extracellular Ca2+ by EGTA, down-regulated SOC entry by small interfering RNA targeting STIM1 or inhibitors targeting Ca2+-binding site of calpain significantly inhibited soft substrate-induced activation of µ-calpain and epithelial cell apoptosis. Thus, soft substrate upregulates the interaction of STIM1 with SOC channels that results in the activation of µ-calpain and subsequently induces normal epithelial cell apoptosis.

Address correspondence to: Meng-Ru Shen (mrshen{at}mail.ncku.edu.tw)






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