Article

Biology of the adenomatous polyposis coli tumor supressor

Howard Hughes Medical Institute, Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 06/2000; 18(9):1967-79.
Source: PubMed

ABSTRACT The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.

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    • "Moreover, heritable changes in the APC gene frequently lead to familial adenomatous polyposis (FAP). FAP is the most dominant inherited syndrome of CRC (88, 89) and Apcmin/+ mice show increased propensity for the development of adenomatous polyps after the loss of the wild type APC allele (88). Up to 80% of sporadic CRCs are known to be initiated by DNA damage of the genes involved in the APC signaling pathway (87). "
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    • "Fewer than 10% of these cases will be in individuals who have an inherited predisposition to the disease, as is the case for familial adenomatous polyposis and hereditary nonpolyposis colon cancer (Goss et al., 2000). There are also other diseases that increased the colorectal cancer risk such as Crohn's diseases and ulcerative colitis. "
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    • "Consequently, other somatic events in APC gene such as intragenic mutations, interstitial deletion, mitotic recombination, and epigenetic silencing of the wild type allele resulting in APC function loss has been proposed as additional mechanisms of intestinal tumorigenesis [57], [58]. Furthermore, reports also suggest that the truncated protein from the mutated allele may exert a dominant negative effect on the full-length protein from the wild type allele of the APC gene resulting in a non-functional APC protein [16]. Currently, efforts are underway in our laboratory to understand frequency and characteristics of 56Fe radiation-induced LOH at the APC locus on mouse chromosome 18 in F1 AKRxC57BL/6 J-ApcMin/+ hybrid mice, commonly used for such studies [60]. "
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