Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nu¨rnberg, Glu¨ckstrasse 6, 91054 Erlangen,Germany.
Hum Mol Genet. 2011 Sep 15;20(18):3554-64. doi: 10.1093/hmg/ddr273. Epub 2011 Jun 10.
The germline transmission of a mutation in the adenomatous polyposis coli (APC) gene leads to cancer of the gastro-intestinal tract upon somatic inactivation of the remaining allele in familial adenomatous polyposis (FAP) patients. APC mutations result in truncated products that have primarily lost the ability to properly regulate the level of the transcription factor β-catenin. However, colorectal cancer cells from FAP patients always retain a truncated APC product and the reasons for this strong selective pressure are not understood. We describe here the surprising property for the transcriptional repressor C-terminal binding protein (CtBP) to promote the oligomerization of truncated APC through binding to the 15 amino acid repeats of truncated APC. CtBP can bind to either first, third or fourth 15 amino acid repeats, but not to the second. CtBP-mediated oligomerization requires both dimerization domains of truncated APC as well as CtBP dimerization. The analysis of the position of the mutations along the APC sequence in adenomas from FAP patients reveals that the presence of the first 15 amino acid repeat is almost always selected in the resulting truncated APC product. This suggests that the sensitivity of truncated APC to oligomerization by CtBP constitutes an essential facet of tumour development.
腺状纤维瘤息肉病（APC）基因中的突变通过体细胞失活导致家族性腺瘤性息肉病（FAP）患者胃肠道癌症。APC 突变导致截断产物，其主要丧失了正确调节转录因子β-连环蛋白水平的能力。然而，来自 FAP 患者的结直肠癌细胞总是保留截断的 APC 产物，而这种强烈选择压力的原因尚不清楚。我们在这里描述了转录抑制因子 C 末端结合蛋白（CtBP）的惊人特性，即通过与截断 APC 的 15 个氨基酸重复序列结合来促进截断 APC 的寡聚化。CtBP 可以结合到第一个、第三个或第四个 15 个氨基酸重复序列，但不能结合到第二个。CtBP 介导的寡聚化需要截断 APC 的两个二聚化结构域以及 CtBP 二聚化。对来自 FAP 患者腺瘤中 APC 序列突变位置的分析表明，第一个 15 个氨基酸重复序列的存在几乎总是在产生的截断 APC 产物中被选择。这表明 CtBP 介导的截断 APC 寡聚化的敏感性是肿瘤发展的一个重要方面。
