PMID:16478791

Citation	Park, KS, Jeon, SH, Kim, SE, Bahk, YY, Holmen, SL, Williams, BO, Chung, KC, Surh, YJ and Choi, KY (2006) APC inhibits ERK pathway activation and cellular proliferation induced by RAS. J. Cell. Sci. 119:819-27
Abstract	Inactivating mutations in the adenomatous polyposis coli gene (APC), and activating mutations in RAS, occur in a majority of colorectal carcinomas. However, the relationship between these changes and tumorigenesis is poorly understood. RAS-induced activation of the ERK pathway was reduced by overexpressing APC in DLD-1 colorectal cancer cells. ERK activity was increased by Cre-virus-induced Apc knockout in primary Apc(flox/flox) mouse embryonic fibroblasts, indicating that APC inhibits ERK activity. ERK activity was increased by overexpression and decreased by knock down of beta-catenin. The activation of Raf1, MEK and ERK kinases by beta-catenin was reduced by co-expression of APC. These results indicate that APC inhibits the ERK pathway by an action on beta-catenin. RAS-induced activation of the ERK pathway was reduced by the dominant negative form of TCF4, indicating that the ERK pathway regulation by APC/beta-catenin signaling is, at least, partly caused by effects on beta-catenin/TCF4-mediated gene expression. The GTP loading and the protein level of mutated RAS were decreased in cells with reduced ERK activity as a result of APC overexpression, indicating that APC regulates RAS-induced ERK activation at least partly by reduction of the RAS protein level. APC regulates cellular proliferation and transformation induced by activation of both RAS and beta-catenin signaling.
Links	PubMed Online version:10.1242/jcs.02779
Keywords	Adenomatous Polyposis Coli Protein/physiology; Animals; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases/metabolism; Gene Expression Regulation; Humans; MAP Kinase Signaling System/genetics; MAP Kinase Signaling System/physiology; Mice; NIH 3T3 Cells; Signal Transduction/physiology; TCF Transcription Factors/genetics; TCF Transcription Factors/metabolism; Transcription Factor 7-Like 2 Protein; Transcription Factor AP-1/physiology; beta Catenin/genetics; beta Catenin/metabolism; ets-Domain Protein Elk-1/physiology; ras Proteins/physiology
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