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Regulation of the DLG tumor suppressor by β-catenin

Vanitha Krishna Subbaiah1, Nisha Narayan, Paola Massimi

  • 1International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, Italy.

International Journal of Cancer
|March 7, 2012
PubMed

Insights

Dereguled beta-catenin enhances the degradation of the discs-large (DLG) tumor suppressor, a process linked to tumorigenesis. This beta-catenin-driven DLG turnover inhibits DLG

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Tumor Suppressor Function

Background:

  • The discs-large (DLG) tumor suppressor is crucial for cell polarity and proliferation, acting as a scaffold at cell-cell junctions.
  • DLG interacts with adenomatous polyposis coli (APC), which regulates beta-catenin.
  • Increased beta-catenin activity and decreased DLG expression are observed in various cancers, including breast and colon.

Purpose of the Study:

  • To investigate the direct functional link between beta-catenin activity and DLG expression levels.
  • To elucidate the mechanism by which beta-catenin influences DLG stability and function.
  • To determine if beta-catenin-mediated DLG degradation contributes to tumorigenesis.

Main Methods:

  • Overexpression of beta-catenin to assess its effect on DLG turnover.
  • Proteasome inhibitor treatment to confirm the degradation pathway.
  • siRNA-mediated ablation of endogenous beta-catenin to evaluate DLG stability.
  • Analysis of protein-protein interactions between beta-catenin and DLG.
  • Oncogene cooperation assays to assess DLG's tumor-suppressive capacity.

Main Results:

  • Overexpressed beta-catenin enhances proteasome-dependent turnover of DLG, specifically targeting DLG over other PDZ domain proteins like MAGI-1 and Scribble.
  • siRNA-mediated knockdown of beta-catenin increases DLG stability.
  • Beta-catenin-induced DLG degradation requires direct association and beta-catenin's PDZ binding potential, while DLG's N-terminal sequences and PDZ domains are essential for its turnover.
  • Beta-catenin inhibits the tumor-suppressive function of DLG in an oncogene cooperation assay.

Conclusions:

  • Dereguled beta-catenin directly enhances the degradation of the DLG tumor suppressor via the proteasome.
  • This beta-catenin-driven DLG degradation is a specific mechanism that requires direct protein interaction and specific protein domains.
  • Inhibition of DLG's tumor-suppressive activity by beta-catenin suggests a novel pathway contributing to tumorigenesis.

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