Chemical-induced apoptosis: Formation of the Apaf-1 apoptosome
Chemical-induced apoptosis: Formation of the Apaf-1 apoptosome
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DOI：
10.1081/dmr-120026497
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发表时间：
2003-01-01
影响因子：
5.9
通讯作者：
Cain, K
中科院分区：
文献类型：
--
作者：
Cain, K
许多环境和治疗剂通过诱导细胞色素c从线粒体释放来启动凋亡性细胞死亡，细胞色素c激活Apaf-1（凋亡蛋白酶激活因子-1）。CED-4是线虫细胞程序性死亡过程中的一个重要蛋白质，其蛋白质分子量约为130 kD。优美的细胞色素c激活Apaf-1，Apaf-1寡聚形成约700 - 1400-kDa的半胱天冬酶激活复合物，称为Apaf-1核糖体。半胱天冬酶-9是一种引发剂半胱天冬酶，然后通过CARD-CARD（半胱天冬酶募集结构域）相互作用与Apaf-1结合而被募集到复合物中，形成全酶复合物。随后，Apaf-1/胱天蛋白酶-9全酶复合物通过胱天蛋白酶-9中的活性位点半胱氨酸与作为切割位点的关键天冬氨酸之间的相互作用募集效应物胱天蛋白酶-3，以产生构成胱天蛋白酶-3的活化形式的胱天蛋白酶-3的大小亚基。这启动了负责细胞凋亡执行阶段的半胱天冬酶级联反应。细胞内K+水平、凋亡抑制蛋白XIAP以及至少两种线粒体释放蛋白Smac/DIABLO和Omi/Htra 2（一种丝氨酸蛋白酶）密切调节细胞凋亡体的形成和功能。因此，许多生理学机制确保了当细胞可避免地死亡时，线粒体复合物才完全组装和发挥功能。有趣的是，最近的研究表明，各种小分子可以通过干扰溶酶体复合物的形成和功能来直接激活或抑制caspase激活。许多常规化疗药物的细胞毒性依赖于它们诱导肿瘤小体形成和凋亡的能力。这一途径的缺陷可能导致耐药性，而小分子可以直接激活或抑制核糖体的发现可能为癌症提供新的替代治疗方法。
Many environmental and therapeutic agents initiate apoptotic cell death by inducing the release of cytochrome c from the mitochondria, which activates Apaf-1 (apoptotic protease-activating factor-1). This large (-l30kD) protein is a mammalian homologue of CED-4, an essential protein involved in programmed cell death in the nematode C. elegans. Cytochrome c activates Apaf-1, which oligomerizes to form an -700-1400-kDa caspase-activating complex known as the Apaf-1 apoptosome. Caspase-9, an initiator caspase, is then recruited to the complex by binding to Apaf-1 through CARD-CARD (caspase recruitment domain) interactions to form a holoenzyme complex. Subsequently, the Apaf-1/ caspase-9 holoenzyme complex recruits the effector caspase-3 via an interaction between the active site cysteine in caspase-9 and the critical aspartate, which is the cleavage site, for generating the large and small subunits of caspase-3 that constitute the activated form of caspase-3. This initiates the caspase cascade that is responsible for the execution phase of apoptosis. Intracellular levels of K+, XIAP an inhibitor of apoptosis protein, and at least two mitochondrial released proteins, Smac/DIABLO and Omi/Htra 2 a serine protease, tightly regulate formation and function of the apoptosome. Thus, a number of physiological mechanisms ensure that the apoptosome complex is only fully assembled and functional when the cell is irrevocably committed to die. It is interesting that more recent studies show that a variety of small molecules can directly activate or inhibit caspase activation by interfering with the formation and function of the apoptosome complex. The cytotoxicity of many conventional chemotherapeutic drugs rests on their ability to induce apoptosome formation and apoptosis. Defects in this pathway can result in drug resistance, and the discovery that small molecules can directly activate or inhibit the apoptosome may provide new alternative treatments for cancer.