P120-catenin is a cytoplasmic protein directly associated with the cell-cell adhesion molecule Ecadherin in the plasma membrane. Its expression is frequently reduced in carcinoma including oral squamous cell carcinoma (OSCC), but the relationship between p120-catenin and human cancers is unclear. Previous studies have shown that p120-catenin plays important roles in the regulation of proliferation and differentiation of keratinocytes, roles requiring activation of phospholipase C-?1 (PLC-?1). In these cells, extracellular calcium induces the formation of a p120-catenin dependent E-cadherin/catenin complex that recruits and activates phosphatidylinositol 3-kinase (PI3K). PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 in the plasma membrane then recruits and activates PLC-?1, which by hydrolyzing PIP2 to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) causes an increase in intracellular calcium leading to keratinocyte differentiation. Expression of p120-catenin is reduced in carcinoma cells. Many studies, including ours, have also shown that PLC-?1 mediates epidermal growth factor receptor (EGFR) induced cell proliferation. Expression of PLC-?1 has been found to be elevated in carcinoma cells. These observations have led us to the hypothesis that p120-catenin functions as a tumor suppressor inhibiting OSCC formation by competing with the oncogene EGFR for PLC-?1 activation. The mechanism and location of PLC-?1 activation determine the delicate balance between differentiation and proliferation of keratinocytes. To address this hypothesis, we propose the following specific aims: (1) Determine whether mice lacking p120-catenin are predisposed to carcinogen-induced OSCC formation. (2) Determine whether p120-catenin and EGFR signaling pathways regulate each other. These studies will uncover a tumor suppressor role for p120-catenin in OSCC and provide assessment of predisposing conditions to carcinogenesis, better prevention, better diagnosis, and better treatment of the disease.

Public Health Relevance

p120-catenin is a cytoplasmic protein directly associated with the cell-cell adhesion molecule E- cadherin in the plasma membrane and its expression is frequently reduced in carcinoma cells including oral squamous cell carcinoma (OSCC), but the relationship between p120-catenin and human cancers is unclear. These studies will determine the tumor suppressor role for p120-catenin and provide insight into the mechanism by which p120-catenin protects cells from the development of OSCC. Understanding this mechanism will bring the possibility of new preventive and therapeutic options for OSCC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DE019529-01A2
Application #
7737094
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Shirazi, Yasaman
Project Start
2009-08-01
Project End
2011-06-30
Budget Start
2009-08-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$232,500
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
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