The adenomatous polyposis coli (APC) tumor suppressor is a gatekeeper that functions to regulate cell growth by controlling the stability and activity of other proteins associated with cell division, cell attachment, and signalling (1). In fact, the APC gene is most often associated with maintaining intestinal epithelial homeostasis, including control of cell extrusion from the epithelium.
The APC gene is localized to chromosome 5q21, which produces a 312 kDa protein consisting of multiple domains having different cellular functions. The large central region of APC containing consists of four 15-a.a. repeat and seven 20-a.a. repeat segments is implicated in binding and degradation of β-catenin and transcriptional corepressors CIBP1/CIBP2 (2). CtBP1 is known to recruit histone deacetylases for gene silencing and thus regulate the expression of β-catenin target genes.
Mechanisms of Action
The Wnt/β-catenin pathway checks and balances the self-renewal, differentiation, and apoptosis of cells residing in stem cell niches (4). APC negatively regulates the expression of transcription factor β-catenin, whic is responsible for activating transcription of effectors in the Wnt signaling pathway and for initiating proliferation and differentiation of intestinal crypt stem cells. Under Wnt signalling, β-catenin is able to help drive proliferation of crypt cells. As a control mechanism, APC recruits β-catenin to its destruction protein scaffold complex (of axin, casein kinase 1, and GSK-3β) in the absence of Wnt signaling. This enables β-catenin to be destabilized by GSK-3β phosphorylation which targets it for degradation by the proteosome upon association with E3 ubiquitin protein ligase (3). Here is a comprehensive video that explains the Wnt/beta-catenin pathway in normal cells and tumours.
When Things Go Wrong
The most common disease associated with germline mutations in APC tumor suppressor is an autosomal dominant disorder called familial adenomatous polyposis coli (FAP). FAP is a pre-condition for colorectal cancer. An explanation of what FAP is nicely explained in this podcast by Sarah-Jane Shaw from the journal Clinical Genetics. Mutated APCs result in enhanced Wnt signaling, where β-catenins are no longer targeted for degradation. This generally leads β-catenin accumulation and translocation into the nucleus, which continually activates genes for crypt cell proliferation (3).
Most often, APC inactivation is caused by missense mutations, leading to truncated proteins. These mutations generally occur in a region in the 15-a.a. and 20aa repeats called mutation cluster region, which encompasses the β-catenin binding site (2). Mutations at the sequence of the C-terminal domain of APC, however, contribute to chromosome and spindle aberrations that lead to chromosome instability (5).
Tumorigenic APC inactivation does not follow the classical two-hit hypothesis. Instead, a continuum model better explains the relationship between dosage and cancer susceptibility. This has been demonstrated in patient and mouse models. For example, intermediate β-catenin signaling, possibly due to haploinsufficiency in APC mutations, causes the greatest severity of disease resulting in intestinal tumors and the formation of cysts and desmoids. However, for enhanced levels of β-catenin signaling, possibly due to biallelic inactivation of APC, the susceptibility and severity for tumor formation declines. Therefore there seems to be a small window of opportunity for triggering tumor growth before apoptosis occurs at a lower level of APC expression. However, it should be noted that this window is context- and tissue-specific, which varies according to different APC genotypes (2,4).
A TSG Similar to APC
The gene neurofibromin-1 (NF1) produces a protein called neurofibromin in nerve cells and myelinating cells in the nervous system. Neurofibromin is a gatekeeper gene that inhibits ras oncogene activity, which promotes cell proliferation and growth when expressed. It inhibits Ras through its GTP-ase activating domain, promoting the inactive form of Ras, Ras-GDP (6). Similar to APC patients, individuals who inherit a single mutant copy of the NF-1 develop multiple benign tumours (in this case, neurofibromas instead of polyps) due to biallelic inactivation that may become malignant, resulting in tumours such as highly aggressive malignant peripheral nerve sheath tumours (7).
(1) Robets, DM., Probobis, MI., Poulton, JS., Waldmann, JD., Stephenson, EM., Hanna, S., and Peifer, M. (2011) Deconstructing the β-catenin destruction complex: mechanistic roles for tumor suppressor APC in regulating Wnt signaling. MBoC. 22, 1845-1863.
(2) Minde, DP., Anvarian, Z., Rudiger, SGD., and Maurice, MM. (2011) Messing up disorder: how do missense mutations in tumor suppressor protein APC lead to cancer?. Molecular Cancer. 10, 1-9.
(3) Schneikert J., Brauburger, K., Behrens, J. (2011) APC mutations in colorectal tumours from FAP patients are selected fro CtBP-mediated oligomerization of truncated APC. Hum Mol Genet. 20, 3554-64.
(4) Bakker, ERM. Hoekstra, E., Franken, PF., Hevensteijn, W., van Deurzen, CHM., van Veeelen, W., Kuipers, EJ., Smits, R. (2012) β-catenin signaling dosage indicates tissue-specific tumor pre-disposition in Apc-driven cancer. Oncogene.1-7.
(5) Fodde, R., Kuiper, J., Rosenberg, C., Smits, R., Kielman, M., Gasper, C., van Es, JH., Breukel, C., Wiegant, J., Giles, RH., and Clevers, H. (2001) Mutations in the APC tumour suppressor gene causes chromosomal instability. Nature Cell Biology. 3, 433-438.
(6) Corral, T., Jimenez, M., Hernandez-Munoz, I., Perez de Castro, I., and Pellicer, A. (2003). NF1 modulates the effects of Ras oncogenes: evidence of other NF1 function besides its GAP activity. Cell Physiol. 197(2):214-24.
(7) Kluwe, L., Friedrich, R.E., Peiper, M., Friedman, J., and Mautner, V. (2003). Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors. Human Mutation 22(5): 420.