title: The APC network regulates the removal of mutated cells from colonic crypts.
abstract: Self-renewal is essential for multicellular organisms but carries the risk of somatic mutations that can lead to cancer, which is particularly critical for rapidly renewing tissues in a highly mutagenic environment such as the intestinal epithelium. Using computational modeling and in vivo experimentation, we have analyzed how adenomatous polyposis coli (APC) mutations and β-catenin aberrations affect the maintenance of mutant cells in colonic crypts. The increasing abundance of APC along the crypt axis forms a gradient of cellular adhesion that causes more proliferative cells to accelerate their movement toward the top of the crypt, where they are shed into the lumen. Thus, the normal crypt can efficiently eliminate β-catenin mutant cells, whereas APC mutations favor retention. Together, the molecular design of the APC/β-catenin signaling network integrates cell proliferation and migration dynamics to translate intracellular signal processing and protein gradients along the crypt into intercellular interactions and whole-crypt physiological or pathological behavior.
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea.
authors.forename: Je-Hoon
authors.initials: JH
authors.lastname: Song
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Huels
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea. Electronic address: ckh@kaist.ac.kr.
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Cho
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D015820:Cadherins; D051176:beta Catenin