Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Bayern, Germany.
Oncogene. 2010 Mar 18;29(11):1663-71. doi: 10.1038/onc.2009.447. Epub 2009 Dec 7.
The adenomatous polyposis coli (APC) protein is a negative regulator of the mitogenic transcription factor beta-catenin by stimulating its proteasomal degradation. This involves several APC domains, including the binding sites for axin/conductin, the recently described beta-Catenin Inhibitory Domain (CID) and the third 20 amino acid repeat (20R3) that is a beta-catenin-binding site. The four 15 amino acid repeats (15R) and the 20R1 are also beta-catenin-binding sites, but their role in beta-catenin degradation has remained unclear. We show here that binding of beta-catenin to the 15R of APC is necessary and sufficient to target beta-catenin for degradation whereas binding to the 20R1 is neither necessary nor sufficient. The first 15R displays the highest affinity for beta-catenin in the 15R-20R1 module. Biallelic mutations of the APC gene lead tocolon cancer in familial adenomatous polyposis coli (FAP) and result in the synthesis of truncated products lacking domains involved in beta-catenin degradation but still having a minimal length. The analysis of the distribution of truncating mutations along the APC sequence in colorectal tumours from FAP patients revealed that the first 15R is one target of the positive selection of mutations that lead to tumour development.
腺瘤性结肠息肉病（APC）蛋白通过刺激其蛋白酶体降解来负调控有丝分裂原转录因子β-连环蛋白。这涉及到几个 APC 结构域，包括与轴蛋白/康丁结合的位点、最近描述的β-连环蛋白抑制结构域（CID）和第三个 20 个氨基酸重复序列（20R3），它是β-连环蛋白的结合位点。四个 15 个氨基酸重复序列（15R）和 20R1 也是β-连环蛋白的结合位点，但它们在β-连环蛋白降解中的作用仍不清楚。我们在这里表明，APC 中β-连环蛋白与 15R 的结合对于将β-连环蛋白靶向降解是必要且充分的，而与 20R1 的结合既不是必要的也不是充分的。在 15R-20R1 模块中，第一个 15R 对β-连环蛋白具有最高的亲和力。APC 基因的双等位基因突变导致家族性腺瘤性息肉病（FAP）中的结肠癌，并导致合成缺乏参与β-连环蛋白降解的结构域但仍具有最小长度的截断产物。对来自 FAP 患者的结直肠肿瘤中 APC 序列中截断突变的分布进行分析，发现第一个 15R 是导致肿瘤发生的突变正选择的一个靶标。
