A nonsense mutation in the tumour suppressor adenomatous polyposis coli (APC) is sufficient to cause colorectal cancer in humans

940 INTRODUCTION A nonsense mutation in the tumour suppressor adenomatous polyposis coli (APC) is sufficient to cause colorectal cancer in humans and animal models (Nandan and Yang, 2010; Kwong and Dove, 2009). Hereditary and sporadic cancers commonly carry nonsense mutations in APC that result in the expression of Nterminal fragments of the APC protein, so that the protein lacks the more C-terminally located -catenin-, tubulin-, actinand EB1binding domains (Phelps et al., 2009; Näthke, 2004). Tumorigenesis resulting from APC mutations has been attributed mainly to activation of -catenin-regulated transcription (Morin, 1999; Barker et al., 2000). Recent studies have begun to highlight the importance of -catenin-independent functions of APC (Okada et al., 2010; Mili et al., 2008). For instance, the phenotype produced by completely deleting the entire gene from one allele of APC seems to be more severe than that produced when this allele encodes an N-terminal APC fragment [as in APCMin/+ mice or the corresponding individuals with familial adenomatous polyposis (FAP)], despite lower levels of active -catenin being present in mice with the gene deletion (Cheung et al., 2010). Furthermore, individuals with an APC allele that leads to production of an N-terminal APC protein fragment that only contains about 150 amino acids (compared with the 850 amino acids encoded by the APCMin allele) present with a much less severe case of the disease, called attenuated FAP (Spirio et al., 1993; Lamlum, 1999). Our understanding of the nature and impact of additional functions of APC and how direct effects of retained N-APC fragments contribute to its role in tumorigenesis remains incomplete (Phelps et al., 2009; Näthke, 2004). Colorectal cancer usually follows the loss of the second APC allele, through loss of heterozygosity. It was recently shown that stepwise mutations of the two APC alleles resulted in dramatically faster tumorigenesis when compared with simultaneous mutation (Fischer et al., 2011). This suggests that the details of how APC heterozygosity and complete loss is achieved affect the specific phenotype of the resulting tumours and adenoma, consistent with the idea that the specific APC fragments that are expressed contribute to this process. One function that is likely to be differentially affected by the length of N-terminal APC fragments is the ability of APC to regulate cytoskeletal proteins. Based on APC interactions with actin and microtubules, we hypothesized that heterozygosity for APC (as in APCMin/+), characterized by expression of an N-terminal fragment Disease Models & Mechanisms 5, 940-947 (2012) doi:10.1242/dmm.008607