The APC tumor suppressor controls entry into S-phase through its ability to regulate the cyclin D/RB pathway.
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.[1]References
- The APC tumor suppressor controls entry into S-phase through its ability to regulate the cyclin D/RB pathway. Heinen, C.D., Goss, K.H., Cornelius, J.R., Babcock, G.F., Knudsen, E.S., Kowalik, T., Groden, J. Gastroenterology (2002) [Pubmed]
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