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.
Highlights
The adenomatous polyposis coli gene (APC) encodes a key tumor suppressor involved in negative regulation of the canonical Wnt/-catenin signaling cascade (Clevers, 2004; Nathke, 2004)
We examined the possible role of the negative regulator of the Wnt/-catenin pathway, APC, in regulating the Extracellular signal regulated kinase (ERK) pathway activated by oncogenic RAS
APC inhibits RAS-induced AP-1 and ELK1 reporter activities and ERK activity We examined the effect of APC on RAS-L61-induced AP1 (Bernstein and Colburm, 1989; Eisenman and Cooper, 1995) activation to assess the role of APC in RAS-induced cell proliferation and malignant transformation
Summary
The adenomatous polyposis coli gene (APC) encodes a key tumor suppressor involved in negative regulation of the canonical Wnt/-catenin signaling cascade (Clevers, 2004; Nathke, 2004). APC interacts with many components of the Wnt/-catenin signaling pathway, including AXIN, GSK3 and -catenin (Mimori-Kiyosue and Tsukita, 2001), but the key tumor suppressor function of APC involves destabilization of free -catenin (Bienz and Clevers, 2000; Munemitsu et al, 1995). APC mutations occur in the early adenoma stages of colorectal tumorigenesis and are likely to be involved in the initiation of colorectal tumors (Behrens and Lustig, 2004; Kinzler and Vogelstein, 1996; Nathke, 2004). A defective APC allele and an activated Ras gene are sufficient to synergistically cause normal colonic epithelial cells to produce carcinomas (D’Abaco et al, 1996), indicating that APC and RAS signals interact in forming tumors
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