MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8.
MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8.
复制标题
MUC1癌蛋白通过抑制caspase-8的募集来阻断死亡受体介导的凋亡。
DOI：
10.1158/0008-5472.can-08-0464
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Kufe, Donald
中科院分区：
文献类型：
--
作者：
Agata, Naoki;Ahmad, Rehan;Kawano, Takeshi;Raina, Deepak;Kharbanda, Surender;Kufe, Donald
死亡受体超家族的刺激诱导半胱天冬酶-8的活化，从而诱导凋亡反应。MUC 1癌蛋白在多种人类恶性肿瘤中异常过表达，并抑制应激诱导的细胞凋亡。目前的结果表明，MUC 1阻断了肿瘤坏死因子α、TRAIL和FasL对恶性细胞的反应中caspase-8的活化和凋亡。结果表明MUC 1与caspase-8组成型相关。MUC 1胞质结构域（MUC 1-CD）直接结合到催化Cys-360位点上游的胱天蛋白酶-8 p18片段。结果还证明MUC 1-CD在死亡效应子结构域结合FADD。在非恶性上皮细胞中，MUC 1与caspase-8和FADD相互作用，作为对死亡受体刺激的诱导反应。这些相互作用的功能意义得到了MUC 1与胱天蛋白酶-8竞争结合FADD并阻断胱天蛋白酶-8募集至死亡诱导信号复合物的证明的支持。这些研究结果表明，MUC 1是重要的caspase-8活性的生理调节和MUC 1的过度表达，发现在人类恶性肿瘤可能有助于死亡受体信号通路的组成性抑制。
Stimulation of the death receptor superfamily induces the activation of caspase-8 and thereby the apoptotic response. The MUC1 oncoprotein is aberrantly overexpressed by diverse human malignancies and inhibits stress-induced apoptosis. The present results demonstrate that MUC1 blocks activation of caspase-8 and apoptosis in the response of malignant cells to tumor necrosis factor α, TRAIL and FasL. The results show that MUC1 associates constitutively with caspase-8. The MUC1 cytoplasmic domain (MUC1-CD) binds directly to the caspase-8 p18 fragment upstream to the catalytic Cys-360 site. The results also demonstrate that MUC1-CD binds to FADD at the death effector domain. In nonmalignant epithelial cells, MUC1 interacts with caspase-8 and FADD as an induced response to death receptor stimulation. The functional significance of these interactions is supported by the demonstration that MUC1 competes with caspase-8 for binding to FADD and blocks recruitment of caspase-8 to the death-inducing signaling complex. These findings indicate that MUC1 is of importance to the physiologic regulation of caspase-8 activity and that overexpression of MUC1 as found in human malignancies could contribute to constitutive inhibition of death receptor signaling pathways.