CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases.
CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases.
复制标题
CD95 (APO-1/Fas) 诱导 ICE 样蛋白酶下游 SAP 激酶的激活。
作者：
Michael A. Cahill;Michael A. Cahill;Marcus E. Peter;F. Kischkel;A. Chinnaiyan;Vishva M. Dixit;P. H. Krammer;Alfred Nordheim
在不同的T细胞系和B细胞系上激活CD95（APO - 1/Fas），会诱导多种激酶（35千道尔顿、38千道尔顿、46千道尔顿和54千道尔顿）的产生，这些激酶可使c - Jun磷酸化，对组蛋白H1的磷酸化程度则较低。这些激酶的激活不依赖于蛋白质生物合成，且先于凋亡性DNA降解发生。由于多种诱导T细胞和B细胞凋亡的物理或化学诱导剂会激活不同的激酶，因此这种激酶激活模式是CD95激活所特有的。46千道尔顿和54千道尔顿的激酶活性中包含应激活化蛋白激酶家族（JNK/SAPK）的成员。用ICE抑制肽N - 苄氧羰基 - 缬氨酰 - 丙氨酰 - 天冬氨酰 - 氟甲基酮（zVAD - fmk）处理细胞，或使牛痘病毒丝氨酸蛋白酶抑制剂CrmA过表达，可阻止CD95特异性激酶组的激活。然而，尽管ICE样蛋白酶受到抑制，但死亡信号仍能在细胞膜上轻易启动，因为会形成CD95死亡诱导信号复合物（DISC）。因此，我们的研究结果表明，CD95通路中的ICE样蛋白酶在DISC下游、SAP激酶上游发挥作用。
Triggering of CD95 (APO-1/Fas) on different T- and B-cell lines resulted in the induction of a number of kinases (35 kDa, 38 kDa, 46 kDa and 54 kDa) that phosphorylate c-Jun and to a lesser extent Histone H1. Activation of these kinases was independent of protein biosynthesis and preceded apoptotic DNA degradation. The kinase activation pattern was specific for CD95 triggering since a variety of physical or chemical inducers of T- and B-cell apoptosis activated different kinases. The kinase activities at 46 and 54 kDa contained members of the stress-activated family of protein kinases (JNK/SAPK). Activation of the CD95-specific set of kinases was prevented by treating cells with the ICE-inhibiting peptide N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) or by overexpression of the cow pox virus serpin CrmA. However, despite inhibition of ICE-like proteases the death signal was readily initiated at the cell membrane since a CD95 death-inducing signaling complex (DISC) was formed. Thus, our results demonstrate that ICE-like proteases in the CD95 pathway function downstream of the DISC but upstream of SAP kinases.