APC mutations in colorectal tumours from FAP patients are selected for CtBP-mediated oligomerization of truncated APC

• Published in: Human molecular genetics 2011-09, Vol.20 (18), p.3554-3564
• Main Authors: SCHNEIKERT, Jean, BRAUBURGER, Katharina, BEHRENS, Jurgen
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli - genetics; Adenomatous Polyposis Coli - metabolism; Adenomatous Polyposis Coli Protein - chemistry; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Alcohol Oxidoreductases - chemistry; Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Biological and medical sciences; Cell Line; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Dimerization; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Genetics of eukaryotes. Biological and molecular evolution; Humans; Medical sciences; Molecular and cellular biology; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Protein Binding; Protein Multimerization; Protein Structure, Tertiary; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr273

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.