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凋亡蛋白酶激活因子-1(Apaf-1)寡聚形成具有生物活性的约700千道尔顿和约1.4兆道尔顿的无活性凋亡小体复合物。

Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4-MDa apoptosome complexes.

作者信息

Cain K, Bratton S B, Langlais C, Walker G, Brown D G, Sun X M, Cohen G M

机构信息

MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester, LE1 9HN United Kingdom.

出版信息

J Biol Chem. 2000 Mar 3;275(9):6067-70. doi: 10.1074/jbc.275.9.6067.

DOI:10.1074/jbc.275.9.6067
PMID:10692394
Abstract

Apaf-1, by binding to and activating caspase-9, plays a critical role in apoptosis. Oligomerization of Apaf-1, in the presence of dATP and cytochrome c, is required for the activation of caspase-9 and produces a caspase activating apoptosome complex. Reconstitution studies with recombinant proteins have indicated that the size of this complex is very large in the order of approximately 1.4 MDa. We now demonstrate that dATP activation of cell lysates results in the formation of two large Apaf-1-containing apoptosome complexes with M(r) values of approximately 1.4 MDa and approximately 700 kDa. Kinetic analysis demonstrates that in vitro the approximately 700-kDa complex is produced more rapidly than the approximately 1.4 MDa complex and exhibits a much greater ability to activate effector caspases. Significantly, in human tumor monocytic cells undergoing apoptosis after treatment with either etoposide or N-tosyl-l-phenylalanyl chloromethyl ketone (TPCK), the approximately 700-kDa Apaf-1 containing apoptosome complex was predominately formed. This complex processed effector caspases. Thus, the approximately 700-kDa complex appears to be the correctly formed and biologically active apoptosome complex, which is assembled during apoptosis.

摘要

凋亡蛋白酶激活因子-1(Apaf-1)通过与半胱天冬酶-9结合并激活它,在细胞凋亡过程中发挥关键作用。在dATP和细胞色素c存在的情况下,Apaf-1的寡聚化是激活半胱天冬酶-9所必需的,并产生一个激活半胱天冬酶的凋亡小体复合物。重组蛋白的重组研究表明,该复合物的大小非常大,约为1.4兆道尔顿。我们现在证明,细胞裂解物的dATP激活导致形成两种含有Apaf-1的大型凋亡小体复合物,其相对分子质量分别约为1.4兆道尔顿和700千道尔顿。动力学分析表明,在体外,约700千道尔顿的复合物比约1.4兆道尔顿的复合物产生得更快,并且表现出更强的激活效应半胱天冬酶的能力。值得注意的是,在用依托泊苷或N-甲苯磺酰-L-苯丙氨酰氯甲基酮(TPCK)处理后经历凋亡的人肿瘤单核细胞中,主要形成了约700千道尔顿的含有Apaf-1的凋亡小体复合物。该复合物加工效应半胱天冬酶。因此,约700千道尔顿的复合物似乎是在细胞凋亡过程中组装形成的正确且具有生物活性的凋亡小体复合物。

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1
Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4-MDa apoptosome complexes.凋亡蛋白酶激活因子-1(Apaf-1)寡聚形成具有生物活性的约700千道尔顿和约1.4兆道尔顿的无活性凋亡小体复合物。
J Biol Chem. 2000 Mar 3;275(9):6067-70. doi: 10.1074/jbc.275.9.6067.
2
Caspase-3 cleaves Apaf-1 into an approximately 30 kDa fragment that associates with an inappropriately oligomerized and biologically inactive approximately 1.4 MDa apoptosome complex.半胱天冬酶-3将凋亡蛋白酶激活因子-1切割成一个约30 kDa的片段,该片段与一个不适当寡聚化且无生物学活性的约1.4 MDa凋亡小体复合物结合。
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Caspase-7 is directly activated by the approximately 700-kDa apoptosome complex and is released as a stable XIAP-caspase-7 approximately 200-kDa complex.半胱天冬酶-7由约700 kDa的凋亡小体复合物直接激活,并作为稳定的约200 kDa的XIAP-半胱天冬酶-7复合物释放。
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Physiological concentrations of K+ inhibit cytochrome c-dependent formation of the apoptosome.生理浓度的钾离子抑制细胞色素c依赖性凋亡小体的形成。
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Transforming growth factor-beta(1) induces apoptosis in rat FaO hepatoma cells via cytochrome c release and oligomerization of Apaf-1 to form a approximately 700-kd apoptosome caspase-processing complex.转化生长因子-β(1)通过细胞色素c释放以及凋亡蛋白酶激活因子-1(Apaf-1)寡聚化形成约700 kDa的凋亡小体半胱天冬酶加工复合物,从而诱导大鼠FaO肝癌细胞凋亡。
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Caspase activation involves the formation of the aposome, a large (approximately 700 kDa) caspase-activating complex.半胱天冬酶激活涉及凋亡小体的形成,凋亡小体是一种大型(约700 kDa)的半胱天冬酶激活复合物。
J Biol Chem. 1999 Aug 6;274(32):22686-92. doi: 10.1074/jbc.274.32.22686.
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Pro-apoptotic proteins released from the mitochondria regulate the protein composition and caspase-processing activity of the native Apaf-1/caspase-9 apoptosome complex.从线粒体释放的促凋亡蛋白调节天然Apaf-1/半胱天冬酶-9凋亡小体复合物的蛋白质组成和半胱天冬酶加工活性。
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Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex.蛋白酶体抑制剂诱导的B细胞慢性淋巴细胞白血病细胞凋亡涉及细胞色素c的释放和半胱天冬酶的激活,同时伴有形成一个含有凋亡小体复合物的约700 kDa凋亡蛋白酶激活因子-1。
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