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APC inhibits ERK pathway activation and cellular proliferation induced by RAS

Cited 61 time in Web of Science Cited 62 time in Scopus

Park, Ki-Sook; Jeon, Soung Hoo; Kim, Sung-Eun; Bahk, Young-Yil; Holmen, Sheri L.; Williams, Bart O.; Chung, Kwang-Chul; Surh, Young-Joon; Choi, Kang-Yell

Issue Date
The Company of Biologists Ltd.
Journal of Cell Science, Vol.119 No.5, pp.819-827
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 Crevirus-induced Apc knockout in primary Apc(flow/flox) mouse embryonic fibroblasts, indicating that APC inhibits ERK activity. ERK activity was increased by overexpression and decreased by knock down of P-catenin. The activation of Raf1, MEK and ERK kinases by P-catenin was reduced by co-expression of APC. These results indicate that APC inhibits the ERK pathway by an action on P-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 P-catenin signaling.
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  • College of Pharmacy
  • Department of Pharmacy
Research Area Agricultural Sciences


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