Gottlieb R A
Division of Hematology, Department of Molecular & Experimental Medicine MEM 220, The Scripps Research Institute, La Jolla, California 92037, USA.
Drug News Perspect. 2000 Oct;13(8):471-6.
Developmentally programmed cell death in animals is accomplished by the activation of a protease of the caspase family. Caspase activation is an essential feature of apoptosis. In Caenorhabditis elegans, this protease is CED-3, which corresponds to mammalian caspase-3. Caspases comprise a distinct family of cysteine aspartases that are activated by interaction with a co-factor and/or proteolytic processing. Once activated, they cleave targets containing the exposed consensus sequences, including other caspases, protein kinases and structural elements, to achieve the death of the cell. Apoptotic cells undergo a dramatic volume loss accompanied by ionic shifts and cytoplasmic acidification. The cytoskeleton rearranges and the cell membrane undergoes blebbing and phosphatidylserine externalization, thus marking the dying cell for ingestion by phagocytes. In addition to structural changes, mitochondria cease to synthesize ATP, release cytochrome c and other constituents, and lose membrane potential. DNA undergoes endonucleolytic cleavage first into 50-kb fragments, followed by cleavage to oligonucleosomes. Together these biochemical processes achieve the noninflammatory destruction of the cell.
动物体内发育程序所决定的细胞死亡是通过激活半胱天冬酶家族的一种蛋白酶来实现的。半胱天冬酶激活是细胞凋亡的一个基本特征。在秀丽隐杆线虫中，这种蛋白酶是CED-3，它与哺乳动物的半胱天冬酶-3相对应。半胱天冬酶构成了一个独特的半胱氨酸天冬氨酸蛋白酶家族，通过与辅因子相互作用和/或蛋白水解加工而被激活。一旦被激活，它们就会切割含有暴露的共有序列的靶标，包括其他半胱天冬酶、蛋白激酶和结构元件，从而导致细胞死亡。凋亡细胞会经历显著的体积减小，伴随着离子转移和细胞质酸化。细胞骨架重新排列，细胞膜出现起泡和磷脂酰丝氨酸外翻，从而将垂死细胞标记为被吞噬细胞吞噬。除了结构变化外，线粒体停止合成ATP，释放细胞色素c和其他成分，并失去膜电位。DNA首先经历核酸内切酶切割形成50 kb的片段，随后切割成寡核小体。这些生化过程共同实现了细胞的非炎性破坏。
