title: A kinetic model to study the regulation of β-catenin, APC, and Axin in the human colonic crypt.
abstract: The Wnt/[Formula: see text]-catenin pathway plays a crucial role in stem cell renewal and differentiation in the normal human colonic crypt. The balance between [Formula: see text]-catenin and APC along the crypt axis determines its normal functionality. The mechanism that deregulates this balance may give insight into the initiation of colorectal cancer. This is significant because the spatial dysregulation of [Formula: see text]-catenin by the mutated tumor suppressor gene/protein APC in human colonic crypts is responsible for the initiation and growth of colorectal cancer. We consider a regulatory function that promotes APC synthesis within the cell and its effect on the accumulation of the Wnt target protein, [Formula: see text]-catenin. It is evident that an APC gradient exists along the crypt axis; however, the mechanism by which APC expression is regulated within the cell is not well known. We investigate the dynamics of an APC regulatory mechanism with an increased level of Axin at the subcellular level. Model output shows an increase of APC for a diminished Wnt signal, which explains the APC gradient along the crypt. We find that the dynamic interplay between [Formula: see text]-catenin, APC, and Axin produces oscillatory behavior, which is controlled by the Wnt stimulus. In the presence of reduced functional APC, the oscillations are amplified, which suggests that the cell remains in a more proliferative state for longer periods of time. Increased Axin levels (typical of mammalian cells) reduce oscillatory behavior and minimize the levels of [Formula: see text]-catenin within the cell while raising the levels of APC.
authors.affiliation: Department of Mathematics, Trinity College, Hartford, CT, 06106, USA. brooks.emerick@trincoll.edu.
authors.forename: Brooks
authors.initials: B
authors.lastname: Emerick
authors.affiliation: Department of Mathematical Sciences, University of Delaware, Newark, DE, 19711, USA.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Schleiniger
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE, 19711, USA.|Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE, 19713, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Boman
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D060466:Axin Protein / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D055641:Mathematical Concepts; D008954:Models, Biological; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C495270:CTNNB1 protein, human; D051176:beta Catenin
keywords: APC regulation; Colonic crypt; Colorectal cancer; Multiple timescale analysis; Wnt pathway