Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, USA.
PLoS One. 2009 Nov 18;4(11):e7879. doi: 10.1371/journal.pone.0007879.
The differentiation and senescence programs of metazoans play key roles in regulating normal development and preventing aberrant cell proliferation, such as cancer. These programs are intimately associated with both the mitotic and apoptotic pathways. Caspase-8 is an apical apoptotic initiator that has recently been appreciated to coordinate non-apoptotic roles in the cell. Most of these functions are attributed to the catalytic domain, however, the amino-terminal death effector domains (DED)s, which belong to the death domain superfamily of proteins, can also play key roles during development. Here we describe a novel role for caspase-8 DEDs in regulating cell differentiation and senescence. Caspase-8 DEDs accumulate during terminal differentiation and senescence of epithelial, endothelial and myeloid cells; genetic deletion or shRNA suppression of caspase-8 disrupts cell differentiation, while re-expression of DEDs rescues this phenotype. Among caspase-8 deficient neuroblastoma cells, DED expression attenuated tumor growth in vivo and proliferation in vitro via disruption of mitosis and cytokinesis, resulting in upregulation of p53 and induction of differentiation markers. These events occur independent of caspase-8 catalytic activity, but require a critical lysine (K156) in a microtubule-binding motif in the second DED domain. The results demonstrate a new function for the DEDs of caspase-8, and describe an unexpected mechanism that contributes to cell differentiation and senescence.
后生动物的分化和衰老程序在调节正常发育和防止异常细胞增殖（如癌症）方面起着关键作用。这些程序与有丝分裂和细胞凋亡途径密切相关。Caspase-8 是一种顶端凋亡起始因子，最近被认为可以协调细胞中的非凋亡作用。这些功能大多归因于催化结构域，但属于蛋白死亡域超家族的氨基末端死亡效应结构域 (DED) 也可以在发育过程中发挥关键作用。在这里，我们描述了 caspase-8 DED 在调节细胞分化和衰老中的新作用。Caspase-8 DED 在上皮细胞、内皮细胞和髓样细胞的终末分化和衰老过程中积累；caspase-8 的基因缺失或 shRNA 抑制会破坏细胞分化，而 DED 的重新表达则可以挽救这种表型。在 caspase-8 缺陷型神经母细胞瘤细胞中，DED 的表达通过破坏有丝分裂和胞质分裂来减弱体内肿瘤生长和体外增殖，导致 p53 上调和分化标志物诱导。这些事件发生在 caspase-8 催化活性之外，但需要在第二个 DED 结构域中的微管结合基序中的关键赖氨酸 (K156)。结果表明 caspase-8 的 DED 具有新的功能，并描述了一种有助于细胞分化和衰老的意外机制。
