Mignotte B, Vayssiere J L
UPR9061 du CNRS, EA1636 de l'Université de Versailles/Saint-Quentin, Centre de Génétique Moléculaire, Gif-sur-Yvette, France.
Eur J Biochem. 1998 Feb 15;252(1):1-15. doi: 10.1046/j.1432-1327.1998.2520001.x.
Programmed cell death serves as a major mechanism for the precise regulation of cell numbers and as a defense mechanism to remove unwanted and potentially dangerous cells. Despite the striking heterogeneity of cell death induction pathways, the execution of the death program is often associated with characteristic morphological and biochemical changes, and this form of programmed cell death has been termed apoptosis. Genetic studies in Caenorhabditis elegans had led to the identification of cell death genes (ced). The genes ced-3 and ced-4 are essential for cell death; ced-9 antagonizes the activities of ced-3 and ced-4, and thereby protects cells that should survive from any accidental activation of the death program. Caspases (cysteine aspartases) are the mammalian homologues of CED-3. CED-9 protein is homologous to a family of many members termed the Bcl-2 family (Bcl-2s) in reference to the first discovered mammalian cell death regulator. In both worm and mammalian cells, the antiapoptotic members of the Bcl-2 family act upstream of the execution caspases somehow preventing their proteolytic processing into active killers. Two main mechanisms of action have been proposed to connect Bcl-2s to caspases. In the first one, antiapoptotic Bcl-2s would maintain cell survival by dragging caspases to intracellular membranes (probably the mitochondrial membrane) and by preventing their activation. The recently described mammalian protein Apaf-1 (apoptosis protease-activating factor 1) could be the mammalian equivalent of CED-4 and could be the physical link between Bcl-2s and caspases. In the second one, Bcl-2 would act by regulating the release from mitochondria of some caspases activators: cytochrome c and/or AIF (apoptosis-inducing factor). This crucial position of mitochondria in programmed cell death control is reinforced by the observation that mitochondria contribute to apoptosis signaling via the production of reactive oxygen species. Although for a long time the absence of mitochondrial changes was considered as a hallmark of apoptosis, mitochondria appear today as the central executioner of programmed cell death. In this review, we examine the data concerning the mitochondrial features of apoptosis. Furthermore, we discuss the possibility that the mechanism originally involved in the maintenance of the symbiosis between the bacterial ancestor of the mitochondria and the host cell precursor of eukaryotes, provided the basis for the actual mechanism controlling cell survival.
程序性细胞死亡是精确调控细胞数量的主要机制，也是清除不需要的和潜在危险细胞的防御机制。尽管细胞死亡诱导途径存在显著的异质性，但死亡程序的执行通常与特征性的形态和生化变化相关，这种形式的程序性细胞死亡被称为凋亡。秀丽隐杆线虫的遗传学研究已导致细胞死亡基因（ced）的鉴定。ced-3和ced-4基因对细胞死亡至关重要；ced-9拮抗ced-3和ced-4的活性，从而保护应存活的细胞免受死亡程序的任何意外激活。半胱天冬酶（半胱氨酸天冬氨酸蛋白酶）是CED-3的哺乳动物同源物。CED-9蛋白与一个被称为Bcl-2家族（Bcl-2s）的多成员家族同源，该家族以第一个发现的哺乳动物细胞死亡调节因子命名。在蠕虫和哺乳动物细胞中，Bcl-2家族的抗凋亡成员在执行半胱天冬酶的上游起作用，以某种方式阻止它们被蛋白水解加工成活性杀手。已经提出了两种主要的作用机制来将Bcl-2s与半胱天冬酶联系起来。在第一种机制中，抗凋亡的Bcl-2s通过将半胱天冬酶拖到细胞内膜（可能是线粒体膜）并阻止其激活来维持细胞存活。最近描述的哺乳动物蛋白Apaf-1（凋亡蛋白酶激活因子1）可能是CED-4的哺乳动物等效物，并且可能是Bcl-2s与半胱天冬酶之间的物理联系。在第二种机制中，Bcl-2通过调节一些半胱天冬酶激活剂从线粒体的释放来发挥作用：细胞色素c和/或AIF（凋亡诱导因子）。线粒体在程序性细胞死亡控制中的这一关键地位因以下观察结果而得到加强，即线粒体通过产生活性氧参与凋亡信号传导。尽管长期以来线粒体变化的缺失被认为是凋亡的一个标志，但如今线粒体似乎是程序性细胞死亡的核心执行者。在这篇综述中，我们研究了有关凋亡线粒体特征的数据。此外，我们讨论了最初参与维持线粒体细菌祖先与真核生物宿主细胞前体之间共生关系的机制为控制细胞存活的实际机制提供基础的可能性。
