Target genes of β-catenin–T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas

Abstract

Mutations in the adenomatous polyposis coli or ␤-catenin gene lead to cytosolic accumulation of ␤-catenin and, subsequently, to increased transcriptional activity of the ␤-catenin-T cell-factor/lymphoid-enhancer-factor complex. This process seems to play an essential role in the development of most colorectal carcinomas. To identify genes activated by ␤-catenin overexpression, we used colorectal cell lines for transfection with the ␤-catenin gene and searched for genes differentially expressed in the transfectants. There are four genes affected by ␤-catenin overexpression; three overexpressed genes code for two components of the AP-1 transcription complex, c-jun and fra-1, and for the urokinase-type plasminogen activator receptor (uPAR), whose transcription is activated by AP-1. The direct interaction of the ␤-catenin-T cell-factor͞lymphoid-enhancerfactor complex with the promoter region of c-jun and fra-1 was shown in a gel shift assay. The concomitant increase in ␤-catenin expression and the amount of uPAR was confirmed in primary colon carcinomas and their liver metastases at both the mRNA and the protein levels. High expression of ␤-catenin in transfectants, as well as in additionally analyzed colorectal cell lines, was associated with decreased expression of ZO-1, which is involved in epithelial polarization. Thus, accumulation of ␤-catenin indirectly affects the expression of uPAR in vitro and in vivo. Together with the other alterations, ␤-catenin accumulation may contribute to the development and progression of colon carcinoma both by dedifferentiation and through proteolytic activity.

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

“…In addition, Qiao et al (2004) reported that IGF-1 stimulates the activity of the transcription factor RUNX2, through a PI3K-dependent but Akt-independent signaling pathway. Both Fra-1 and Runx2 are known downstream targets of the Wnt or cat/TCF signaling pathway (Mann et al, 1999;Dong et al, 2006). In this study, we found that insulin stimulates PAK-1 phosphorylation/activation in multiple cancer cell lines and in mouse intestinal tissues on Thr423, a target residue of phosphoinositide-dependent kinase isozyme-1, hence bypassing Akt (King et al, 2000).…”

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

“…Examples include BIRC7, L1CAM, PLAUR and FGF18, which are all downstream targets of Wnt/bcatenin signaling (Mann et al, 1999;Shimokawa et al, 2003;Gavert et al, 2005;Yuan et al, 2007). PLAUR and SERPINE1 are components of the urokinase plasminogen activator system, and the overexpression of these genes has been correlated with a high-grade tumor and poor survival outcomes in RCC (Swiercz et al, 1998;Ohba et al, 2005).…”

Tumors from rats given 1,2-dimethylhydrazine plus chlorophyllin or indole-3-carbinol contain transcriptional changes in β-catenin that are independent of β-catenin mutation status

“…Indeed, β-catenin mRNA levels are known to be increased in human primary colorectal cancers and their liver metastases, compared with matched normal-looking tissue [5]. A major regulator of β-catenin expression in human colon cancers is APC, but this is usually viewed from the perspective of β-catenin protein stabilization rather than transcriptional control of β-catenin mRNA levels.…”

“…Cytosolic β-catenin interacts with APC, Axin, glycogen synthase kinase-3β (GSK-3β) and other protein partners, leading to phosphorylation of Ser33, Ser37, Thr41 and Ser45 residues in the N-terminal region of β-catenin, followed by ubiquitination and proteosomal degradation [1][2][3]. In primary human colon tumors and colorectal cancer cell lines, mutations in CTNNB1 substitute one of the four critical Ser/Thr residues and stabilize β-catenin, leading to accumulation of β-catenin/TCF complexes in the nucleus, and activation of downstream target genes [4][5][6].…”