Chen C Y, Juo P, Liou J S, Li C Q, Yu Q, Blenis J, Faller D V
Cancer Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Cell Growth Differ. 2001 Jun;12(6):297-306.
Oncogenic Ras induces cells to undergo apoptosis after inhibition of protein kinase C (PKC) activity. The integration of differential signaling pathways is required for full execution of apoptosis. In this study, we used Jurkat as well as Fas/FADD-defective cell lines expressing v-ras to determine the upstream elements required for activation of the caspase cascade in PKC/Ras-mediated apoptosis. During this Ras-induced apoptotic process, caspase-8 was activated, possibly through its binding to Fas-associated death domain (FADD), in Jurkat/ras and Jurkat/Fas(m)/ras cells but not in Jurkat/FADD(m)/ras cells. c-Jun NH(2)-terminal kinase (JNK) was activated in all three cell lines expressing ras in response to apoptotic stimulation. Suppression of JNK by dn-JNK1 blocked the interaction of FADD and caspase-8 and partially protected Jurkat/ras and Jurkat/Fas(m)/ras cells from apoptosis. However, dn-JNK1 had no effect on PKC/Ras-induced apoptosis in Jurkat/FADD(m)/ras cells. The results indicate that FADD/caspase-8 signaling is involved in PKC/Ras-mediated apoptosis, and JNK may be an upstream effector of caspase activation.
致癌性Ras在抑制蛋白激酶C（PKC）活性后诱导细胞发生凋亡。凋亡的完全执行需要不同信号通路的整合。在本研究中，我们使用Jurkat细胞以及表达v-ras的Fas/FADD缺陷细胞系来确定PKC/Ras介导的凋亡中激活半胱天冬酶级联反应所需的上游元件。在这种Ras诱导的凋亡过程中，半胱天冬酶-8在Jurkat/ras和Jurkat/Fas(m)/ras细胞中被激活，可能是通过其与Fas相关死亡结构域（FADD）结合，但在Jurkat/FADD(m)/ras细胞中未被激活。c-Jun氨基末端激酶（JNK）在所有三种表达ras的细胞系中响应凋亡刺激而被激活。通过dn-JNK1抑制JNK可阻断FADD与半胱天冬酶-8的相互作用，并部分保护Jurkat/ras和Jurkat/Fas(m)/ras细胞免于凋亡。然而，dn-JNK1对Jurkat/FADD(m)/ras细胞中PKC/Ras诱导的凋亡没有影响。结果表明，FADD/半胱天冬酶-8信号传导参与PKC/Ras介导的凋亡，并且JNK可能是半胱天冬酶激活的上游效应器。
