Apoptosis Protection by Mcl-1 and Bcl-2 Modulation of Inositol 1,4,5-Trisphosphate Receptor-dependent Ca2+ Signaling

被引:147
作者
Eckenrode, Emily F. [1 ]
Yang, Jun [2 ]
Velmurugan, Gopal V. [1 ]
Foskett, J. Kevin [2 ,3 ]
White, Carl [1 ]
机构
[1] Rosalind Franklin Univ Med & Sci, Dept Physiol & Biophys, N Chicago, IL 60064 USA
[2] Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA
[3] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
CELL PROLIFERATION; OLIGOMERIZES BAK; CALCIUM-RELEASE; BCL-X(L); ER; TRANSDUCTION; INVOLVEMENT; ACTIVATION; PROTEINS; BINDING;
D O I
10.1074/jbc.M109.096040
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Members of the Bcl-2 protein family play a central role in the regulation of apoptosis. An interaction between anti-apoptotic Bcl-x(L) and the endoplasmic reticulum (ER)-localized inositol trisphosphate receptor Ca2+ release channel (InsP(3)R) enables Bcl-x(L) to be fully efficacious as an anti-apoptotic mediator (White, C., Li, C., Yang, J., Petrenko, N. B., Madesh, M., Thompson, C. B., and Foskett, J. K. (2005) Nat. Cell Biol. 7, 1021-1028). Physiologically, Bcl-x(L) binds to the InsP(3)R to enhance its gating and Ca2+ signaling. Here we have discovered that structurally related proteins Bcl-2 and Mcl-1 function similarly. Bcl-2, Mcl-1 and Bcl-x(L) bind with comparable affinity to the carboxyl termini of all three mammalian InsP(3)R isoforms with important functional consequences. Stable expression of Bcl-2 or Mcl-1 lowered ER Ca2+ content and enhanced the rate of InsP(3)-mediated Ca2+ release in response to submaximal InsP(3) stimulation in permeabilized wild-type DT40 cells but not in cells lacking InsP(3)R. In addition, expression of either Bcl-2 or Mcl-1 enhanced spontaneous InsP(3)R-dependent Ca2+ oscillations and spiking in intact cells in the absence of agonist stimulation. Bcl-2- and Mcl-1-mediated protection from apoptosis induced by staurosporine or etoposide was enhanced in cells expressing InsP(3)R, demonstrating that their interactions with InsP(3)R enable Bcl-2 and Mcl-1 to be fully efficacious anti-apoptotic mediators. Our data suggest a molecular mechanism that is shared by several anti-apoptotic Bcl-2 proteins that provides apoptosis resistance by direct interactions at the ER with the InsP(3)R that impinges on cellular Ca2+ homeostasis.
引用
收藏
页码:13678 / 13684
页数:7
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