The RIP-like kinase, RIP3, induces apoptosis and NF-κB nuclear translocation and localizes to mitochondria
The RIP-like kinase, RIP3, induces apoptosis and NF-κB nuclear translocation and localizes to mitochondria
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DOI：
10.1016/s0014-5793(00)01473-3
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发表时间：
2000-05-19
期刊：
影响因子：
3.5
通讯作者：
Gomes, BC
中科院分区：
文献类型：
--
作者：
Kasof, GM;Prosser, JC;Gomes, BC
RIP样蛋白RIP 3最近被报道含有一个N-末端激酶结构域和一个新的C-末端结构域，其促进细胞凋亡。这些实验进一步表征了RIP 3介导的细胞凋亡和NF-κ B活化。北方印迹表明，rip 3 mRNA显示出有限的表达模式，包括成人中枢神经系统的区域。通过荧光原位杂交将rip 3基因定位于人类染色体14q11.2，该区域在几种类型的肿瘤中经常改变。RIP 3介导的细胞凋亡被Bcl-2、Bcl-x（L）、显性负性FADD以及一般半胱天冬酶抑制剂Z-VAD抑制。对参与RIP 3诱导的细胞凋亡的半胱天冬酶的进一步分析表明，更特异性的抑制剂Z-DEVD（半胱天冬酶-3、-6、-7、-8和-10）和Z-VDVAD（半胱天冬酶-2）的抑制。caspase-1、caspase-6、caspase-8和caspase-9抑制剂对RIP 3介导的细胞凋亡影响很小或没有影响。RIP 3的突变分析表明，RIP 3的C端参与了其凋亡活性。该区域与许多促凋亡受体和衔接蛋白（包括FAS、FADD、TNFR 1和RIP）中发现的死亡结构域相似但不同。此外，在死亡结构域之间保守的氨基酸的RIP 3的点突变，废除其凋亡活性。RIP 3通过免疫荧光定位于线粒体，并且可能在通常与细胞凋亡相关的线粒体破坏中起关键作用。(C)2000年欧洲生物化学学会联合会。
A RIP-like protein, RIP3, has recently been reported that contains an N-terminal kinase domain and a novel C-terminal domain that promotes apoptosis. These experiments further characterize RIP3-mediated apoptosis and NF-kappa B activation. Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system. The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia. RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-x(L), dominant-negative FADD, as well as the general caspase inhibitor Z-VAD. Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2). However, caspase-1, -6, -8 and -9 inhibitors had little or no effect on RIP3-mediated apoptosis, Mutational analysis of RIP3 revealed that the C-terminus of RIP3 contributed to its apoptotic activity. This region is similar, but distinct, to the death domain found in many pro-apoptotic receptors and adapter proteins, including FAS, FADD, TNFR1, and RIP. Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity. RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis. (C) 2000 Federation of European Biochemical Societies.