Genetics

FAP is an autosomal dominant disease with almost complete penetrance by 40 years of age. APC germline mutations are the only known cause of FAP.

Gene structure and expression

The APC gene was localized to chromosome 5q21-22 by Bodmer et al. {156} and Leppert et al. {1047}. It was isolated by the group of White {868; 629} and by the laboratories of Naka-mura and Vogelstein {920; 1364}. It spans over a region of 120 Kb and is composed of at least 21 exons, 7 of which are alternatively expressed {1658}. 16 APC transcripts that differ in their 5'-most regions and arise by the alternative inclusion of 6 of these exons have been identified. The APC gene is ubiquitously expressed in normal tissues, with highest levels in the central nervous system. Tissue-specific differences were observed in the expression of APC transcripts without exon 1, a coding region for a heptad repeat that supports homodimerization of the APC protein.

Gene product and function

The APC protein is a 2,843-amino acid polypeptide that is a negative regulator in the Wnt signaling pathway. The protein contains several functional domains that act as binding and degradation sites for p-catenin and control the p-catenin intra-cellular concentration. A protein-binding domain near the carboxy-terminal of APC mediates phosphorylation by glycogen synthase kinase 3 p (GSK3b) and stabilizes the formation of a complex between the two proteins {1627}. In an unstimulated cell, GSK3b promotes phosphorylation of the protein conductin/axin which is added to the APC GSK3b complex {2107; 124}. Phosphorylated axin recruits p-catenin, which is in turn phosphorylated and targeted for degradation through an APC-dependent ubiquitin-proteasome pathway {11}. Normal Wnt signalling inhibits GSK3b activity and dephosphory-lates axin. As a result, p-catenin is released from the complex {2107}. In the cytoplasm, p-catenin is involved in cytoskeletal organization with binding to microtubules. It also interacts with E-cad-herin, a membrane protein involved in cell adhesion. Free p-catenin shuttles to the nucleus where it binds to the transcription factors of the TCF/LEF family. The resulting complexes activate c-MYC {680} and cyclin D1 transcription {1753; 1922}. Lack of functional APC causes unregulated intracellular accumulation of p-catenin and thereby constitutive expression of c-MYC and of the cyclin D1 gene (CDD1).

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