Abstract
SUMMARYNonsense mutations that result in the expression of truncated, N-terminal, fragments of the adenomatous polyposis coli (APC) tumour suppressor protein are found in most sporadic and some hereditary colorectal cancers. These mutations can cause tumorigenesis by eliminating β-catenin-binding sites from APC, which leads to upregulation of β-catenin and thereby results in the induction of oncogenes such as MYC. Here we show that, in three distinct experimental model systems, expression of an N-terminal fragment of APC (N-APC) results in loss of directionality, but not speed, of cell motility independently of changes in β-catenin regulation. We developed a system to culture and fluorescently label live pieces of gut tissue to record high-resolution three-dimensional time-lapse movies of cells in situ. This revealed an unexpected complexity of normal gut cell migration, a key process in gut epithelial maintenance, with cells moving with spatial and temporal discontinuity. Quantitative comparison of gut tissue from wild-type mice and APC heterozygotes (APCMin/+; multiple intestinal neoplasia model) demonstrated that cells in precancerous epithelia lack directional preference when moving along the crypt-villus axis. This effect was reproduced in diverse experimental systems: in developing chicken embryos, mesoderm cells expressing N-APC failed to migrate normally; in amoeboid Dictyostelium, which lack endogenous APC, expressing an N-APC fragment maintained cell motility, but the cells failed to perform directional chemotaxis; and multicellular Dictyostelium slug aggregates similarly failed to perform phototaxis. We propose that N-terminal fragments of APC represent a gain-of-function mutation that causes cells within tissue to fail to migrate directionally in response to relevant guidance cues. Consistent with this idea, crypts in histologically normal tissues of APCMin/+ intestines are overpopulated with cells, suggesting that a lack of migration might cause cell accumulation in a precancerous state.
Highlights
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)
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)
Individuals with an APC allele that leads to production of an N-terminal APC protein fragment that only contains about 150 amino acids present with a much less severe case of the disease, called attenuated FAP (Spirio et al, 1993; Lamlum, 1999)
Summary
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-, actin- and EB1binding domains (Phelps et al, 2009; Näthke, 2004). 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). 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)
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