Hamada Fumihiko, Bienz Mariann
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.
Dev Cell. 2004 Nov;7(5):677-85. doi: 10.1016/j.devcel.2004.08.022.
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.
腺瘤性结肠息肉病蛋白（APC）是结肠中一种重要的肿瘤抑制因子。APC通过促进β-连环蛋白的核输出及其在细胞质中的蛋白酶体降解，来拮抗Wnt效应因子β-连环蛋白的转录活性。在此，我们表明APC拮抗β-连环蛋白的第三种功能涉及C端结合蛋白（CtBP）。APC在体内与CtBP相关联，并在体外通过其保守的15个氨基酸重复序列与CtBP结合。这种关联的缺失会导致β-连环蛋白/TCF复合物水平以及TCF介导的转录水平升高。值得注意的是，CtBP在体内既不与TCF相关联，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的直接共抑制因子这一观点提出了质疑。我们的证据表明，APC是β-连环蛋白和CtBP之间的衔接子，并且CtBP通过隔离APC/β-连环蛋白复合物，降低了游离核β-连环蛋白与TCF结合的可用性。
