Activation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APC

Abstract

Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by beta-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta-catenin.

Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers

“…One was identified in an adenoma where codon 45, a serine, was deleted (S45Del). This deletion of a phosphorylation site was reported by Morin et al21 as an activating mutation. The other two mutations were nonsense mutations identified in carcinomas (R95X and Q773X).…”

“…Thus, it is logical that a truncated SOX9 could lead to an accumulation of β‐catenin. CTNNB1 mutations have been described in colon cancer that activate β‐catenin and make it insensitive to wt APC 21. Inhibition by wt APC is mediated through phosphorylation of serine/threonine residues.…”

The αE-catenin gene (CTNNA1) acts as an invasion-suppressor gene in human colon cancer cells

“…The E-cadherin gene acts as an invasion-suppressor gene in lobular breast cancer since mutation of one allele in combination with loss of the other allele leads to invasive tumours . b-Catenin acts as an oncogene in colon cancer and in melanoma since heterozygous mutation results in protein stabilization and correlates with tumour progression (Morin et al, 1997;Rubinfeld et al, 1997). For aE-catenin the e ect on tumour progression of heterozygous as compared to homozygous mutations has not been examined.…”

Variable mutation frequencies in coding repeats of TCF-4 and other target genes in colon, gastric and endometrial carcinoma showing microsatellite instability

“…This has now been extended to a total of 104 samples of which 35 (33.5%) showed a 1 bp deletion in this repeat. TCF-4 is a transcription factor which upregulates expression of c-MYC (He et al, 1998) as well as the expression of several other genes when complexed with b-catenin Morin et al, 1997). Due to its high frequency of mutation, we have proposed that this deletion event is selected for and plays an important role in MSI-H colorectal carcinogenesis (Duval et al, 1999).…”