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The beta-catenin binding domain of adenomatous polyposis coli is sufficient for tumor suppression
Abstract:
Inactivation of the adenomatous polyposis coli (APC) gene is a critical event in the development of human colorectal cancers. At the biochemical level, several functions have been assigned to the multidomain APC protein, but the cellular effects of APC expression and how they relate to its biochemical functions are less well defined. To address these issues, we generated a recombinant adenovirus (Ad-CBR) that constitutively expresses the central third of APC, which includes all of the known beta-catenin binding repeats. When expressed in colon cancer cells, Ad-CBR blocked the nuclear translocation of beta-catenin and inhibited beta-catenin/Tcf-4-mediated transactivation. Accordingly, expression of endogenous targets of the APC/beta-catenin/Tcf-4 pathway was down-regulated. Ad-CBR infection of colorectal cancer cell lines with mutant APC but wild-type beta-catenin resulted in substantial growth arrest followed by apoptosis. These effects were attenuated in lines with wild-type APC but with mutated beta-catenin. These findings suggest that the beta-catenin-binding domain in the central third of APC is sufficient for its tumor suppressor activity.
Insights
Inactivating the adenomatous polyposis coli (APC) gene drives colorectal cancer. The APC protein's beta-catenin binding domain is sufficient for tumor suppression, halting cancer cell growth and causing apoptosis.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- Adenomatous polyposis coli (APC) gene inactivation is crucial in human colorectal cancer development.
- The cellular functions of the multidomain APC protein and their relation to its biochemical roles are not fully understood.
Purpose of the Study:
- To investigate the cellular effects of APC expression and its relation to biochemical functions.
- To determine if the beta-catenin binding domain of APC is sufficient for tumor suppressor activity.
Main Methods:
- Generated a recombinant adenovirus (Ad-CBR) for constitutive expression of APC's central third (beta-catenin binding repeats).
- Infected colorectal cancer cell lines with mutant APC and wild-type beta-catenin, and vice versa.
- Assessed beta-catenin nuclear translocation, Tcf-4-mediated transactivation, target gene expression, cell growth, and apoptosis.
Main Results:
- Ad-CBR expression blocked beta-catenin nuclear translocation and inhibited beta-catenin/Tcf-4 transactivation.
- Down-regulation of endogenous targets in the APC/beta-catenin/Tcf-4 pathway was observed.
- Infection induced significant growth arrest and apoptosis in cells with mutant APC and wild-type beta-catenin, with attenuated effects in cells with wild-type APC and mutated beta-catenin.
Conclusions:
- The beta-catenin-binding domain within the central third of APC is sufficient for its tumor suppressor function.
- Targeting the APC/beta-catenin/Tcf-4 pathway holds potential for colorectal cancer therapy.