title: Regulation of the DLG tumor suppressor by β-catenin.
abstract: The discs-large (DLG) tumor suppressor plays essential roles in regulating cell polarity and proliferation. It localizes at sites of cell-cell contact where it acts as a scaffold for multiple protein interactions, including with the adenomatous polyposis coli (APC) tumor suppressor, which in turn regulates β-catenin. Furthermore, many tumor types including breast and colon have increased levels of β-catenin activity with correspondingly low levels of DLG expression. Here we provide evidence of a direct functional link between these apparently separate phenomena. We show that overexpressed β-catenin can enhance the turnover of DLG in a proteosome dependent manner. This effect is specific to DLG and is not seen with two other PDZ domain-containing targets of β-catenin, MAGI-1 and Scribble. Furthermore, siRNA-mediated ablation of endogenous β-catenin expression also enhances DLG stability. β-catenin-induced degradation of DLG appears to be a consequence of a direct association between the two proteins and requires β-catenin PDZ binding potential. In contrast, the enhanced turnover of DLG requires the unique N-terminal sequences and its PDZ domains. Finally, we also show that the capacity of DLG to inhibit transformed cell growth in an oncogene cooperation assay is inhibited by β-catenin. Taken together these studies suggest that one mechanism by which deregulated β-catenin can contribute to tumorigenesis is through enhancing DLG degradation.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, Italy.
authors.forename: Vanitha Krishna
authors.initials: VK
authors.lastname: Subbaiah
authors.forename: Nisha
authors.initials: N
authors.lastname: Narayan
authors.forename: Paola
authors.initials: P
authors.lastname: Massimi
authors.forename: Lawrence
authors.initials: L
authors.lastname: Banks
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex