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Gastroenterology. 2002 Sep;123(3):751-63.

The APC tumor suppressor controls entry into S-phase through its ability to regulate the cyclin D/RB pathway.

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Howard Hughes Medical Institute, Department of Molecular Genetics, University of Cincinnati College of Medicine, Ohio 45267-0524, USA.



APC gene mutation is an early alteration in most colorectal tumors. In an attempt to determine its role in tumor development, we asked whether reintroducing wild-type APC into colorectal cancer cells with mutant APC affected cell cycle progression.


Using transient transfection, a plasmid containing the APC complementary DNA and DNA encoding the green fluorescent protein was expressed in SW480 cells. In addition, several other constructs were co-expressed with APC to determine their combined effects.


We report that colorectal cancer cell lines transfected with wild-type APC arrest in the G(1)- phase of the cell cycle and that this arrest is abrogated by cotransfecting constitutively active beta-catenin or cyclin D1 and cMYC together. This APC-induced cell cycle arrest involves the disruption of beta-catenin-mediated transcription and depends on components of the G(1)/S regulatory machinery, as overexpression of E1a or E2F-1, -2, or -3 overrides the G(1) arrest. Consistent with this, APC transfection inhibits RB phosphorylation and reduces levels of cyclin D1.


Our results suggest that APC functions upstream of RB in the G(1)/S regulatory pathway, cyclin D1 and cMYC affect APC-mediated arrest equivalently to oncogenic beta-catenin, and most colon tumors disrupt control of G(1)/S progression by APC mutation.

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