Germline APC Mutation on the β-Catenin Binding Site Is Associated with a Decreased Apoptotic Level in Colorectal Adenomas

Abstract

Germline mutations in APC tumor suppressor gene are responsible for familial adenomatous polyposis (FAP). A major role of these genetic changes is the constitutive activation of ␤-catenin-Tcf-4 mediated transcription of nuclear target genes, but other cellular functions can be misregulated. To assess how different APC mutations can drive the early steps of colonic tumorigenesis, we studied the effect of 10 different germline-truncating alterations on the phenotype of the corresponding adenomas. A significant reduction of apoptosis, uncoupled with an increased c-myc and cyclin-D1 expression, was seen with a frameshift mutation on codon 1383, in the 20-aa repeats of the ␤-catenin degradation domain, independent of a somatic alteration on the wildtype allele. The decreased apoptotic level was associated with a higher incidence of cancerization. No other APC mutation was linked with a similar effect, even in presence of a somatic allelic loss. These findings suggest that mutations in critical sites of the ␤-catenin degradation domain of APC gene can convey a selective advantage to the colonic neoplastic clones by altering the apoptotic surveillance rather than enhancing the ␤-catenin-Tcf-4 transcription of growth-promoting genes.

Non-traditional roles for the Adenomatous Polyposis Coli (APC) tumor suppressor protein

“…Similarly, retinal degeneration and apoptosis due to loss of dAPC2 in Drosophila is rescued by expression of Armadillo/β-catenin (Ahmed et al, 1998). However, no increase in nuclear β-catenin staining or expression of the β-catenin/TCF/LEF targets, c-myc and cyclinD1 was observed in FAP patients possessing the 1383 allele of APC suggesting that inappropriate activation of the Wnt pathway may not accompany reduced apoptosis in human colon cancer (Venesio et al, 2003). Thus, in the context of colon cancer further work will be required to understand how loss of APC leads to a decrease in apoptosis.…”

“…Significantly, mutation of APC can exert the opposite effect on apoptosis in the intestinal epithelium. A mutation of APC found in some FAP patients results in expression of a carboxy-terminal truncated APC protein that correlates with a reduction in apoptosis (Venesio et al, 2003). The regulation of apoptosis by APC may be an important part of APC's tumor suppressor function, promoting differentiation and limiting proliferation to maintain colonic homeostasis.…”

Mitochondrial Targeting of Adenomatous Polyposis Coli Protein Is Stimulated by Truncating Cancer Mutations

“…While this may be true in some cases, there is also evidence for transcription-and ␤-catenin-independent mechanisms of APC-dependent apoptosis (23,28,36). APC is susceptible to cleavage by caspases during the early stages of apoptosis (26,37), and is cleaved at aspartate 777 located at the end of the Arm domain (26).…”

Regulatory single nucleotide polymorphisms (rSNPs) at the promoters 1A and 1B of the human APC gene

“…Nowadays, the APC protein is considered a universal tumour suppressor mostly acting as an antagonist of the Wnt signaling pathway [26–28]. Moreover, a growing body of evidence supports the idea that APC performs numerous functions outside the Wnt pathway: e.g., roles in cell migration [29], adhesion [30], chromosome segregation [31], apoptosis [32], and neuronal differentiation [33]. Multifunctionality of the APC protein and the complex expression pattern of its gene [13, 23] are suggestive of fairly complicated organisation of the regulatory regions in the APC gene.…”