Diarylurea compounds inhibit caspase activation by preventing the formation of the active 700-kilodalton apoptosome complex
Diarylurea compounds inhibit caspase activation by preventing the formation of the active 700-kilodalton apoptosome complex
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DOI：
10.1128/mcb.23.21.7829-7837.2003
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发表时间：
2003-11-01
影响因子：
5.3
通讯作者：
Jäättelä, M
中科院分区：
文献类型：
--
作者：
Lademann, U;Cain, K;Jäättelä, M
线粒体促凋亡蛋白释放到胞质溶胶中是凋亡信号传导中的关键事件，导致半胱天冬酶的激活。一旦在细胞质中，细胞色素e触发称为细胞分裂体的半胱天冬酶激活蛋白复合物的形成，而Smac/Diablo和Omi/htra 2拮抗凋亡蛋白抑制剂（IAP）的半胱天冬酶抑制作用。在这里，我们确定二芳基脲化合物作为有效的抑制剂的细胞色素c诱导的活性，约700 kDa的溶酶体复合物和半胱天冬酶激活的形成。使用diarylureas抑制的形成的的线粒体复合物，我们证明，细胞色素c，而不是IAP拮抗剂，是主要的线粒体半胱天冬酶激活因子在肿瘤坏死因子治疗的肿瘤细胞。因此，我们已经鉴定了一类新的化合物，其通过直接抑制细胞凋亡体复合物的形成来阻断引发剂胱天蛋白酶9的活化来抑制细胞凋亡。这种作用机制不同于广泛使用的胱天蛋白酶的四肽抑制剂或已知的内源性凋亡抑制剂（如Bcl-2和IAP）所采用的作用机制。因此，这些化合物提供了一种新的特定的工具，研究的作用，在依赖于死亡范式的线粒体。
The release of mitochondrial proapoptotic proteins into the cytosol is the key event in apoptosis signaling, leading to the activation of caspases. Once in the cytosol, cytochrome e triggers the formation of a caspase-activating protein complex called the apoptosome, whereas Smac/Diablo and Omi/htra2 antagonize the caspase inhibitory effect of inhibitor of apoptosis proteins (IAPs). Here, we identify diarylurea compounds as effective inhibitors of the cytochrome c-induced formation of the active, approximately 700-kDa apoptosome complex and caspase activation. Using diarylureas to inhibit the formation of the apoptosome complex, we demonstrated that cytochrome c, rather than IAP antagonists, is the major mitochondrial caspase activation factor in tumor cells treated with tumor necrosis factor. Thus, we have identified a novel class of compounds that inhibits apoptosis by blocking the activation of the initiator caspase 9 by directly inhibiting the formation of the apoptosome complex. This mechanism of action is different from that employed by the widely used tetrapeptide inhibitors of caspases or known endogenous apoptosis inhibitors, such as Bcl-2 and IAPs. Thus, these compounds provide a novel specific tool to investigate the role of the apoptosome in mitochondrion-dependent death paradigms.