Human Molecular Genetics Advance Access originally published online on April 2, 2008
Human Molecular Genetics 2008 17(13):1978-1987; doi:10.1093/hmg/ddn095
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Functional definition of the mutation cluster region of adenomatous polyposis coli in colorectal tumours
1 Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany 2 Department of Internal Medicine, Cantonal Hospital St Gallen, Rorschacher Strasse 95, 9007 St Gallen, Switzerland
* To whom correspondence should be addressed. Tel: +49 91318529110; Fax: +49 91318529111; Email: jbehrens{at}molmed.uni-erlangen.de
Received February 5, 2008; Accepted March 19, 2008
The mutation cluster region (MCR) of adenomatous polyposis coli (APC) is located within the central part of the open reading frame, overlapping with the region encoding the 20 amino acid repeats (20R) that are β-catenin-binding sites. Each mutation in the MCR leads to the synthesis of a truncated APC product expressed in a colorectal tumour. The MCR extends from the 3' border of the first 20R coding region to approximately the middle of the third 20R coding region, reflecting both positive and negative selections of the N- and C-terminal halves of the APC protein in colon cancer cells, respectively. In contrast, the second 20R escapes selection and can be either included or excluded from the truncated APC products found in colon cancer cells. To specify the functional outcome of the selection of the mutations, we investigated the β-catenin binding capacity of the first three 20R in N-terminal APC fragments. We found in co-immunoprecipitation and intracellular co-localization experiments that the second 20R is lacking any β-catenin binding activity. Similarly, we also show that the tumour-associated truncations abolish the interaction of β-catenin with the third 20R. Thus, our data provide a functional definition of the MCR: the APC fragments typical of colon cancer are selected for the presence of a single functional 20R, the first one, and are therefore equivalent relative to β-catenin binding.
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  E. M. Kohler, S. H. V. Chandra, J. Behrens, and J. Schneikert {beta}-Catenin degradation mediated by the CID domain of APC provides a model for the selection of APC mutations in colorectal, desmoid and duodenal tumours Hum. Mol. Genet., January 15, 2009; 18(2): 213 - 226. [Abstract] [Full Text] [PDF]
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