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First published online 14 February 2006
doi: 10.1242/jcs.02779
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Research Article |
1 Division of Molecular and Cellular Biology, Department of Biotechnology, Yonsei University, Seoul 120-752, Korea
2 Protein Network Research Center, Yonsei University, Seoul 120-752, Korea
3 Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA
4 Department of Biology, Yonsei University, Seoul 120-752, Korea
5 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, Korea
* Author for correspondence (e-mail: kychoi{at}yonsei.ac.kr)
Accepted 3 November 2005
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 Apcflox/flox mouse embryonic fibroblasts, indicating that APC inhibits ERK activity. ERK activity was increased by overexpression and decreased by knock down of ß-catenin. The activation of Raf1, MEK and ERK kinases by ß-catenin was reduced by co-expression of APC. These results indicate that APC inhibits the ERK pathway by an action on ß-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/ß-catenin signaling is, at least, partly caused by effects on ß-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 ß-catenin signaling.
Key words: APC, ß-catenin, ERK, RAS, Transformation, Wnt
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