Regulation of the DLG tumor suppressor by ß-catenin.
Int J Cancer
; 131(10): 2223-33, 2012 Nov 15.
Article
in En
| MEDLINE
| ID: mdl-22392736
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 ß-catenin. Furthermore, many tumor types including breast and colon have increased levels of ß-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 ß-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 ß-catenin, MAGI-1 and Scribble. Furthermore, siRNA-mediated ablation of endogenous ß-catenin expression also enhances DLG stability. ß-catenin-induced degradation of DLG appears to be a consequence of a direct association between the two proteins and requires ß-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 ß-catenin. Taken together these studies suggest that one mechanism by which deregulated ß-catenin can contribute to tumorigenesis is through enhancing DLG degradation.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tumor Suppressor Proteins
/
Beta Catenin
Limits:
Humans
Language:
En
Journal:
Int J Cancer
Year:
2012
Document type:
Article
Affiliation country: