Apoptosis Protection by Mcl-1 and Bcl-2 Modulation of Inositol 1,4,5-Trisphosphate Receptor-dependent Ca2+ Signaling
Apoptosis Protection by Mcl-1 and Bcl-2 Modulation of Inositol 1,4,5-Trisphosphate Receptor-dependent Ca2+ Signaling
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DOI：
10.1074/jbc.m109.096040
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发表时间：
2010-04-30
影响因子：
4.8
通讯作者：
White, Carl
中科院分区：
文献类型：
--
作者：
Eckenrode, Emily F.;Yang, Jun;White, Carl
Bcl2蛋白家族成员在细胞凋亡的调控中起着核心作用。抗细胞凋亡的Bc l-x(L)与内质网(ER)定位的三磷酸肌醇受体钙释放通道(InSP(3)R)之间的相互作用使Bl-x(L)能够完全有效地作为抗细胞凋亡的介体(White，C.，Li，C.，Yang，J.，Petrenko，N.B.，Madesh，M.，Thompson，C.B.和Foskett，J.K.(2005)NAT)。细胞生物。7、1021-1028)。生理上，Bclx(L)与Insp(3)R结合，增强其门控和钙信号转导。在这里，我们发现结构上相关的蛋白Bcl-2和Mcl-1的功能相似。Bcl2、Mcl-1和Bclx(L)与所有三种哺乳动物Insp(3)R亚型的羧基末端具有相似的亲和力，具有重要的功能。在通透性野生型DT40细胞中，Bcl2或Mcl-1的稳定表达降低了内质网钙离子含量，提高了Insp(3)介导的钙释放速率，但在缺乏Insp(3)R的细胞中没有。此外，在没有激动剂刺激的情况下，Bcl2或Mcl-1的表达增强了Insp(3)R依赖的自发性钙振荡和完整细胞的尖峰。在表达Insp(3)R的细胞中，bcl-2和Mcl-1对星形孢子素或依托泊苷诱导的细胞凋亡的保护作用增强，表明它们与Insp(3)R的相互作用使bcl-2和Mcl-1成为完全有效的抗凋亡介质。我们的数据提示了一种分子机制，该机制是由几种抗凋亡的Bcl-2蛋白共享的，通过在内质网与Insp(3)R直接相互作用来提供对细胞钙稳态的抵抗。
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.