PED/PEA-15:: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis
PED/PEA-15:: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis
复制标题
DOI：
10.1038/sj.onc.1202831
复制
发表时间：
1999-08-05
期刊：
影响因子：
8
通讯作者：
Beguinot, F
中科院分区：
文献类型：
--
作者：
Condorelli, G;Vigliotta, G;Beguinot, F
FED/PEA-15是最近克隆的一个分子量为15 kDa的蛋白，具有死亡效应结构域（death effector domain，DED）。在MCF-7和HeLa细胞中，PED/PEA-15的五倍过表达阻断了Fast和TNF α。凋亡效应这种FED过表达的影响被PKC活性的抑制所阻断。在MCF-7和HeLa细胞裂解物中，PED/ PEA-15与FADD和FLICE共沉淀。PED/PEA-15-FLICE关联被野生型的过表达抑制，但不被FADD的DED缺失突变体的过表达抑制。PED/ PEA-15与FADD和FLICE的同时过表达抑制FADD-FLICE共沉淀三倍。基于FLICE底物PARP的裂解，这种抑制作用被响应于TNF-α的FLICE活化的三倍下降所抵消。TNF α，反过来，减少FED与细胞的内源性FADD和FLICE的关联。因此，FED/PEA-15是抑制FAS和TNFR 1介导的细胞凋亡的内源性蛋白。至少部分地，该功能可能涉及通过PED/PEA-15的死亡效应结构域置换FADD-FLICE结合。
FED/PEA-15 is a recently cloned 15kDa protein possessing a death effector domain (DED). In MCF-7 and HeLa cells, a fivefold overexpression of PED/PEA-15 blocked Fast and TNF alpha. apoptotic effects. This effect of FED overexpression was blocked by inhibition of PKC activity. In MCF-7 and HeLa cell lysates, PED/ PEA-15 co-precipitated with both FADD and FLICE. PED/PEA-15-FLICE association was inhibited by overexpression of the wild-type but not of a DED-deletion mutant of FADD. Simultaneous overexpression of PED/ PEA-15 with FADD and FLICE inhibited FADD-FLICE co-precipitation by threefold. Based on cleavage of the FLICE substrate PARP, this inhibitory effect was paralleled by a threefold decline in FLICE activation in response to TNF-alpha. TNF alpha, in turn, reduces FED association with the endogenous FADD and FLICE of the cells. Thus, FED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis. At least in part, this function may involve displacement of FADD-FLICE binding through the death effector domain of PED/PEA-15.