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The beta-catenin binding domain of adenomatous polyposis coli is sufficient for tumor suppression

I M Shih1, J Yu, T C He

  • 1Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.

Cancer Research
|April 5, 2000
PubMed

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.

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