Harvey K J, Blomquist J F, Ucker D S
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago 60612, USA.
Mol Cell Biol. 1998 May;18(5):2912-22. doi: 10.1128/MCB.18.5.2912.
Physiological cell deaths occur ubiquitously throughout biology and have common attributes, including apoptotic morphology with mitosis-like chromatin condensation and prelytic genome digestion. The fundamental question is whether a common mechanism of dying underlies these common hallmarks of death. Here we describe evidence of such a conserved mechanism in different cells induced by distinct stimuli to undergo physiological cell death. Our genetic and quantitative biochemical analyses of T- and B-cell deaths reveal a conserved pattern of requisite components. We have dissected the role of cysteine proteases (caspases) in cell death to reflect two obligate classes of cytoplasmic activities functioning in an amplifying cascade, with upstream interleukin-1beta-converting enzyme-like proteases activating downstream caspase 3-like caspases. Bcl-2 spares cells from death by punctuating this cascade, preventing the activation of downstream caspases while leaving upstream activity undisturbed. This observation permits an operational definition of the stages of the cell death process. Upstream steps, which are necessary but not themselves lethal, are modulators of the death process. Downstream steps are effectors of, and not dissociable from, actual death; the irreversible commitment to cell death reflects the initiation of this downstream phase. In addition to caspase 3-like proteases, the effector phase of death involves the activation in the nucleus of cell cycle kinases of the cyclin-dependent kinase (Cdk) family. Nuclear recruitment and activation of Cdk components is dependent on the caspase cascade, suggesting that catastrophic Cdk activity may be the actual effector of cell death. The conservation of the cell death mechanism is not reflected in the molecular identity of its individual components, however. For example, we have detected different cyclin-Cdk pairs in different instances of cell death. The ordered course of events that we have observed in distinct cases reflects essential thematic elements of a conserved sequence of modulatory and effector activities comprising a common pathway of physiological cell death.
生理性细胞死亡在整个生物学领域普遍存在，且具有共同特征，包括具有有丝分裂样染色质浓缩的凋亡形态以及溶细胞前的基因组消化。根本问题在于，是否存在一种共同的死亡机制作为这些共同死亡特征的基础。在此，我们描述了在不同细胞中由不同刺激诱导发生生理性细胞死亡时存在这种保守机制的证据。我们对T细胞和B细胞死亡进行的遗传及定量生化分析揭示了所需成分的保守模式。我们剖析了半胱氨酸蛋白酶（胱天蛋白酶）在细胞死亡中的作用，以反映在放大级联反应中起作用的两类必需的细胞质活性，上游白细胞介素-1β转化酶样蛋白酶激活下游的胱天蛋白酶3样胱天蛋白酶。Bcl-2通过打断这一级联反应使细胞免于死亡，它能阻止下游胱天蛋白酶的激活，同时不干扰上游活性。这一观察结果为细胞死亡过程的阶段提供了一个可操作的定义。上游步骤是死亡过程的调节因子，虽必不可少但本身并不致命。下游步骤是实际死亡的效应器，与实际死亡不可分离；对细胞死亡的不可逆承诺反映了这一下游阶段的启动。除了胱天蛋白酶3样蛋白酶外，死亡的效应阶段还涉及细胞周期蛋白依赖性激酶（Cdk）家族的细胞周期激酶在细胞核中的激活。Cdk成分的核募集和激活依赖于胱天蛋白酶级联反应，这表明灾难性的Cdk活性可能是细胞死亡的实际效应器。然而，细胞死亡机制的保守性并未体现在其各个成分的分子特性上。例如，我们在不同的细胞死亡实例中检测到了不同的细胞周期蛋白-Cdk对。我们在不同案例中观察到的有序事件过程反映了由生理性细胞死亡共同途径组成的保守调节和效应活性序列的基本主题元素。
