The APC tumor suppressor binds to C-terminal binding protein to divert nuclear β-catenin from TCF
The APC tumor suppressor binds to C-terminal binding protein to divert nuclear β-catenin from TCF
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DOI：
10.1016/j.devcel.2004.08.022
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发表时间：
2004-11-01
影响因子：
11.8
通讯作者：
Bienz, M
中科院分区：
文献类型：
--
作者：
Hamada, F;Bienz, M
腺瘤性结肠息肉病 (APC) 是结肠中重要的肿瘤抑制因子。 APC 通过促进其核输出和细胞质中的蛋白酶体破坏来拮抗 Wnt 效应子 β-连环蛋白的转录活性。在这里，我们证明 APC 拮抗 β-连环蛋白的第三个功能涉及 C 端结合蛋白 (CtBP)。 APC 在体内与 CtBP 相关，并在体外通过其保守的 15 个氨基酸重复序列与 CtBP 结合。这种关联的失败会导致 β-连环蛋白/TCF 复合物和 TCF 介导的转录水平升高。值得注意的是，CtBP 在体内既不与 TCF 相关，TCF-4 中 CtBP 结合基序的突变也不会改变其转录活性。这对 CtBP 是 TCF 的直接辅阻遏物的观点提出了质疑。我们的证据表明，APC 是 β-连环蛋白和 CtBP 之间的接头，并且 CtBP 通过隔离 APC/β-连环蛋白复合物来降低游离核 β-连环蛋白与 TCF 结合的可用性。
Adenomatous polyposis coli (APC) is an important tumor suppressor in the colon. APC antagonizes the transcriptional activity of the Wnt effector beta-catenin by promoting its nuclear export and its proteasomal destruction in the cytoplasm. Here, we show that a third function of APC in antagonizing beta-catenin involves C-terminal binding protein (CtBP). APC is associated with CtBP in vivo and binds to CtBP in vitro through its conserved 15 amino acid repeats. Failure of this association results in elevated levels of beta-catenin/TCF complexes and of TCF-mediated transcription. Notably, CtBP is neither associated with TCF in vivo nor does mutation of the CtBP binding motifs in TCF-4 alter its transcriptional activity. This questions the idea that CtBP is a direct corepressor of TCF. Our evidence indicates that APC is an adaptor between beta-catenin and CtBP and that CtBP lowers the availability of free nuclear beta-catenin for binding to TCF by sequestering APC/beta-catenin complexes.