Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during CD95- and anticancer drug-induced apoptosis.
Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during CD95- and anticancer drug-induced apoptosis.
复制标题
DOI：
10.1084/jem.188.5.979
复制
发表时间：
1998-09-07
期刊：
影响因子：
--
通讯作者：
Schulze-Osthoff K
中科院分区：
文献类型：
--
作者：
Ferrari D;Stepczynska A;Los M;Wesselborg S;Schulze-Osthoff K
细胞凋亡由不同的刺激诱导，其中包括死亡受体 CD95、十字孢菌素和化疗药物的触发。在所有情况下，细胞凋亡都是由半胱天冬酶介导的，尽管尚不清楚这些不同的细胞凋亡刺激如何引起蛋白酶激活。最近发现了两条调控途径，但尚不清楚它们在功能上是独立的还是相互关联的。一种是通过将近端调节因子 caspase-8 招募到死亡受体复合物来介导。另一条途径由线粒体释放细胞色素 c 以及随后死亡调节因子凋亡蛋白酶激活因子 1 (Apaf-1) 的 ATP 依赖性激活来控制。在这里，我们报告这两种途径都可以通过细胞内 ATP 的消耗来分解。阻止 ATP 产生可完全抑制化疗药物和十字孢菌素引起的 caspase 激活和细胞凋亡。有趣的是，caspase-8 的功能似乎仅限于死亡受体，在正常条件下也能被这些药物激活，但在 ATP 耗尽后不会被激活。相反，抑制 ATP 产生并不影响触发 CD95 后 caspase 的激活。这些结果表明化疗药物诱导的 caspase 激活完全由受体独立的线粒体途径控制，而 CD95 诱导的细胞凋亡可以由不需要 Apaf-1 功能的单独途径调节。
Apoptosis is induced by different stimuli, among them triggering of the death receptor CD95, staurosporine, and chemotherapeutic drugs. In all cases, apoptosis is mediated by caspases, although it is unclear how these diverse apoptotic stimuli cause protease activation. Two regulatory pathways have been recently identified, but it remains unknown whether they are functionally independent or linked to each other. One is mediated by recruitment of the proximal regulator caspase-8 to the death receptor complex. The other pathway is controlled by the release of cytochrome c from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Here, we report that both pathways can be dissected by depletion of intracellular ATP. Prevention of ATP production completely inhibited caspase activation and apoptosis in response to chemotherapeutic drugs and staurosporine. Interestingly, caspase-8, whose function appeared to be restricted to death receptors, was also activated by these drugs under normal conditions, but not after ATP depletion. In contrast, inhibition of ATP production did not affect caspase activation after triggering of CD95. These results suggest that chemotherapeutic drug–induced caspase activation is entirely controlled by a receptor-independent mitochondrial pathway, whereas CD95-induced apoptosis can be regulated by a separate pathway not requiring Apaf-1 function.
登录
查看更多内容
DOI：
10.1073/pnas.93.25.14486
发表时间：
1996-12-10
影响因子：
11.1
作者：
Srinivasula, SM;Ahmad, M;Alnemri, ES
通讯作者：
Alnemri, ES
影响因子：
4.1
作者：
Kass, GEN;Eriksson, JE;Chow, SC
通讯作者：
Chow, SC
影响因子：
11.4
作者：
Medema, JP;Scaffidi, C;Peter, ME
通讯作者：
Peter, ME
影响因子：
64.5
作者：
Boldin, MP;Goncharov, TM;Wallach, D
通讯作者：
Wallach, D
影响因子：
4.8
作者：
Adachi, S;Cross, AR;Gottlieb, RA
通讯作者：
Gottlieb, RA