The APC gene encodes a ubiquitously expressed 300 kDa protein that is frequently mutated in patients suffering from FAP and GS.
APC is associated with structural components of intracellular junctions, including conductin, and it competes with E-cadherin for binding to specific internal regions of both â- and ã-catenin.
Like APC, APC2 contains SAMP domains, which are required for conductin binding. Both APC and APC2 regulate the formation of active â-catenin-Tcf complexes.
Germ line mutations in the tumor suppressor gene adenomatous polyposis coli (APC) cause familial adenomatous polyposis (FAP).
regulating beta-catenin, an important mediator of cell adhesion and a transcriptional activator.
cytoskeletal regulation
Pathology
germline mutations of APC in
- familial adenomatous polyposis
- Gardner syndrome
- medulloblastoma-associated Turcot syndrome
truncation mutations in the adenomatous polyposis coli protein (APC) are responsible for familial and sporadic colonic tumours
somatic inactivation of the APC gene
- sporadic hepatocellular carcinoma (16897741)
Physiopathology
The mutations in the APC gene found in FAP lead to a disturbed function of the APC protein. The key tumor suppressor function of APC is to regulate the stability and cellular localization of β-catenin.
β-catenin is a bifunctional protein; it is has a crucial role in cell-cell adhesion and a signaling role in the Wnt pathway. Loss of functional APC in tumorigenesis deregulates the signaling properties of β-catenin, leading to cytosolic accumulation and nuclear translocation. In the nucleus, it activates transcriptional targets such as c-myc and cyclin D1.
In cell adhesion, β-catenin is crucial to the normal functioning of E-cadherin. E-cadherin, the main adhesion molecule of epithelial cells, is a calcium-dependent transmembrane glycoprotein mediating cell-cell adhesion.
Intracellular β-catenin binds to the cytoplasmic tail of E-cadherin, forming an adhesion complex with the actin cytoskeleton. E-cadherin/catenin complexes are also involved in differentiation, polarity, migration, proliferation, and survival of epithelial cells, which are all fundamental processes for the maintenance of normal intestinal epithelial architecture and function.
Animal models
APC min/+ mouse
Mouse mode in which the adenomatous polyposis colon (Apc) tumour-suppressor gene carries a truncating mutation, resulting in a defective protein. These mice develop several benign polyps (adenomas) of the colon.
See also
WNT signaling pathway
cadherin-catenin complex
References
Katoh H, Shibata T, Kokubu A, Ojima H, Kosuge T, Kanai Y, Hirohashi S. Genetic inactivation of the APC gene contributes to the malignant progression of sporadic hepatocellular carcinoma: a case report. Genes Chromosomes Cancer. 2006 Nov;45(11):1050-7. PMID: 16897741
Reviews
Nathke I. Cytoskeleton out of the cupboard: colon cancer and cytoskeletal changes induced by loss of APC. Nat Rev Cancer. 2006 Dec;6(12):967-74. PMID: 17093505
Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC. Hum Mol Genet. 2001 Apr;10(7):721-33. PMID: 11257105
Dikovskaya D, Zumbrunn J, Penman GA, Nathke IS. The adenomatous polyposis coli protein: in the limelight out at the edge. Trends Cell Biol. 2001 Sep;11(9):378-84. PMID: 11514192