Basu S, Bayoumy S, Zhang Y, Lozano J, Kolesnick R
Laboratory of Signal Transduction, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Biol Chem. 1998 Nov 13;273(46):30419-26. doi: 10.1074/jbc.273.46.30419.
Prior investigations document that proliferative signaling cascades, under some circumstances, initiate apoptosis, although mechanisms that dictate the final outcome are largely unknown. In COS-7 cells, ceramide signals Raf-1 activation through Ras (Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., McGinley, M., Chan-Hui, P. Y., Lichenstein, H., and Kolesnick, R. (1997) Cell 89, 63-72), but not apoptosis. However, expression of small amounts of the pro-apoptotic Bcl-2 family member, BAD, conferred ceramide-induced apoptosis onto COS-7 cells. Ceramide signaled apoptosis in BAD-expressing cells by a pathway involving sequentially kinase suppressor of Ras (KSR)/ceramide-activated protein kinase, Ras, c-Raf-1, and MEK1. Downstream, this pathway linked to BAD dephosphorylation at serine 136 by prolonged inactivation of Akt/PKB. Further, mutation of BAD at serine 136 abrogated ceramide signaling of apoptosis. The present study indicates that when ceramide signals through the Ras/Raf cascade, the availability of a single target, BAD, may dictate an apoptotic outcome.
先前的研究表明，在某些情况下，增殖信号级联会引发细胞凋亡，尽管决定最终结果的机制在很大程度上尚不清楚。在COS-7细胞中，神经酰胺通过Ras信号传导Raf-1激活（Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., McGinley, M., Chan-Hui, P. Y., Lichenstein, H., and Kolesnick, R. (1997) Cell 89, 63 - 72），但不会引发细胞凋亡。然而，少量促凋亡Bcl-2家族成员BAD的表达使COS-7细胞发生神经酰胺诱导的细胞凋亡。神经酰胺通过一条依次涉及Ras激酶抑制因子（KSR）/神经酰胺激活蛋白激酶、Ras、c-Raf-1和MEK1的信号通路，在表达BAD的细胞中引发细胞凋亡。在下游，该信号通路通过Akt/PKB的长期失活与BAD丝氨酸136位点的去磷酸化相关联。此外，BAD丝氨酸136位点的突变消除了神经酰胺诱导的细胞凋亡信号。本研究表明，当神经酰胺通过Ras/Raf级联信号传导时，单个靶点BAD的可用性可能决定细胞凋亡的结果。
