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首页> 外文期刊>Oncogene >Caspase cleavage of the APC tumor suppressor and release of an amino-terminal domain is required for the transcription-independent function of APC in apoptosis
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Caspase cleavage of the APC tumor suppressor and release of an amino-terminal domain is required for the transcription-independent function of APC in apoptosis

机译：Caspase裂解APC肿瘤抑制因子和释放氨基末端结构域是APC凋亡中与转录无关的功能所必需的

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The adenomatous polyposis coli (APC) tumor suppressor is inactivated by mutation in most colorectal tumors. APC is a component of the Wnt signaling pathway and is best known for its ability to downregulate -catenin and consequent effects on transcriptional regulation. Previous work demonstrated that APC accelerates apoptosis-associated caspase activity independently of transcription, and suggested novel tumor suppressor functions of APC. In this work, we have mapped the APC apoptosis-accelerating region to amino acids (aa) 1–760 by testing a series of non-overlapping APC segments. Interestingly, this segment corresponds to a stable group II caspase cleavage product of APC released during apoptosis that includes the amino-terminal aa1–777. Mutation of the APC aspartic acid residue at position 777 to an alanine completely abolished in vitro cleavage of APC by a recombinant group II caspase and rendered the full-length protein unable to accelerate apoptosis in vitro. A truncated APC protein associated with familial and sporadic colorectal cancer, also unable to accelerate apoptosis in vitro and in vivo, is resistant to group II caspase cleavage. These results demonstrate that cleavage of APC and the subsequent release of an amino-terminal segment are necessary for the transcription-independent mechanism of APC-mediated apoptosis.
机译：腺瘤性息肉病大肠杆菌（APC）抑癌药通过大多数大肠肿瘤的突变而失活。 APC是Wnt信号通路的组成部分，以其下调-catenin的能力及其对转录调控的影响而闻名。先前的研究表明，APC可以独立于转录来加速凋亡相关的caspase活性，并提示APC具有新颖的肿瘤抑制功能。在这项工作中，我们通过测试一系列不重叠的APC区段，将APC凋亡加速区域映射到了氨基酸（aa）1–760。有趣的是，该片段对应于APC在凋亡过程中释放的稳定的II组caspase裂解产物，包括氨基末端aa1-777。 777位的APC天冬氨酸残基突变为丙氨酸，完全消除了重组II型半胱天冬酶对APC的体外裂解，使全长蛋白无法在体外加速细胞凋亡。与家族性和散发性结直肠癌相关的截短的APC蛋白，也不能在体外和体内加速细胞凋亡，对II组半胱天冬酶裂解具有抵抗力。这些结果表明，APC介导的凋亡的转录独立机制是必需的，APC的裂解和随后的氨基末端片段的释放。

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