Lindenboim Liora, Schlipf Sarah, Kaufmann Thomas, Borner Christoph, Stein Reuven
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
Exp Cell Res. 2004 Jul 15;297(2):392-403. doi: 10.1016/j.yexcr.2004.03.001.
Bcl-x(S), a pro-apoptotic member of the Bcl-2 protein family, is localized in the mitochondrial outer membrane and induces caspase-dependent and nerve growth factor (NGF)-inhibitable apoptosis in PC12 cells. The mechanism of action of Bcl-x(S) and how NGF inhibits this death are not fully understood. It is still unknown whether Bcl-x(S) induces mitochondrial cytochrome c release, and which apoptotic step NGF inhibits. We show that Bcl-x(S) induces cytochrome c release and caspase-3 activation in several cell types, and that in PC12 cells, these events are inhibited by NGF treatment. The survival effect of NGF was inhibited by inhibitors of protein kinase C (PKC), phosphatidylinositol-3-kinase (PI 3-kinase), and the mitogen-activated protein kinase kinase (MEK) inhibitors GF109203X, LY294002, and U0126. These findings show that cytochrome c release and caspase-3 activation participate in Bcl-x(S)-induced apoptosis, and that NGF inhibits Bcl-x(S)-induced apoptosis at the mitochondrial level via the PKC, PI 3-kinase, and MEK signaling pathways.
Bcl-x(S)是Bcl-2蛋白家族的一个促凋亡成员，定位于线粒体外膜，可诱导PC12细胞发生半胱天冬酶依赖性且神经生长因子（NGF）可抑制的凋亡。Bcl-x(S)的作用机制以及NGF如何抑制这种细胞死亡尚未完全明确。目前仍不清楚Bcl-x(S)是否会诱导线粒体细胞色素c释放，以及NGF抑制的是凋亡的哪一步骤。我们发现，Bcl-x(S)在多种细胞类型中均可诱导线粒体细胞色素c释放和半胱天冬酶-3激活，而在PC12细胞中，这些事件会被NGF处理所抑制。蛋白激酶C（PKC）抑制剂、磷脂酰肌醇-3激酶（PI 3-激酶）抑制剂以及丝裂原活化蛋白激酶激酶（MEK）抑制剂GF109203X、LY294002和U0126均可抑制NGF的存活效应。这些研究结果表明，细胞色素c释放和半胱天冬酶-3激活参与了Bcl-x(S)诱导的凋亡过程，并且NGF通过PKC、PI 3-激酶和MEK信号通路在线粒体水平抑制Bcl-x(S)诱导的凋亡。
