TY - JOUR
T1 - Requirement of biphasic calcium release from the endoplasmic reticulum for Fas-mediated apoptosis
AU - Wozniak, Ann L.
AU - Wang, Xinmin
AU - Stieren, Emily S.
AU - Scarbrough, Shelby G.
AU - Elferink, Cornelis J.
AU - Boehning, Darren
PY - 2006/12
Y1 - 2006/12
N2 - Fas receptor is a member of the tumor necrosis factor-α family of death receptors that mediate physiologic apoptotic signaling. To investigate the molecular mechanisms regulating calcium mobilization during Fas-mediated apoptosis, we have analyzed the sequential steps leading to altered calcium homeostasis and cell death in response to activation of the Fas receptor. We show that Fas-mediated apoptosis requires endoplasmic reticulum-mediated calcium release in a mechanism dependent on phospholipase C-γ1 (PLC-γ1) activation and Ca2+ release from inositol 1,4,5-trisphosphate receptor (IP3R) channels. The kinetics of Ca2+ release were biphasic, demonstrating a rapid elevation caused by PLC-γ1 activation and a delayed and sustained increase caused by cytochrome c binding to IP 3R. Blocking either phase of Ca2+ mobilization was cytoprotective, highlighting PLC-γ1 and IP3R as possible therapeutic targets for disorders associated with Fas signaling.
AB - Fas receptor is a member of the tumor necrosis factor-α family of death receptors that mediate physiologic apoptotic signaling. To investigate the molecular mechanisms regulating calcium mobilization during Fas-mediated apoptosis, we have analyzed the sequential steps leading to altered calcium homeostasis and cell death in response to activation of the Fas receptor. We show that Fas-mediated apoptosis requires endoplasmic reticulum-mediated calcium release in a mechanism dependent on phospholipase C-γ1 (PLC-γ1) activation and Ca2+ release from inositol 1,4,5-trisphosphate receptor (IP3R) channels. The kinetics of Ca2+ release were biphasic, demonstrating a rapid elevation caused by PLC-γ1 activation and a delayed and sustained increase caused by cytochrome c binding to IP 3R. Blocking either phase of Ca2+ mobilization was cytoprotective, highlighting PLC-γ1 and IP3R as possible therapeutic targets for disorders associated with Fas signaling.
UR - http://www.scopus.com/inward/record.url?scp=33845288349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845288349&partnerID=8YFLogxK
U2 - 10.1083/jcb.200608035
DO - 10.1083/jcb.200608035
M3 - Article
C2 - 17130290
AN - SCOPUS:33845288349
SN - 0021-9525
VL - 175
SP - 709
EP - 714
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
ER -