The sodium pump (Na,K-ATPase), a heterodimer consisting of an a- and a 13-subunit, plays a central role in kidney functions. We showed that the b-subunit of this enzyme was drastically reduced in the most common and aggressive form of kidney cancer, the clear-cell renal cell carcinoma. We now provide evidences that the 13-subunit of Na,K-ATPase play a key role in the cell adhesion mechanisms leading to the polarization of kidney epithelial cells and suppression of invasion and motility of carcinoma cells. E-cadherin is a cell adhesion molecule implicated in cell adhesion, maintenance of the polarized epithelial phenotype, and invasion suppression of carcinoma cells. Over-expression of E-cadherin in Moloney Sarcoma Virus-transformed Madin-Darby Canine Kidney (MSV-MDCK) cells did not alter their fibroblast-like phenotype and invasiveness. However, co-expression of the 13-subunit of Na,K-ATPase and E-cadherin in MSV-MDCK cells resulted in the reversion of the fibroblast-like phenotype to a well-differentiated epithelial phenotype including formation of tight junctions and loss of invasiveness. These studies strongly indicate that E-cadherins' cell adhesion function alone is not sufficient to regulate polarity and invasion suppression of kidney epithelial cells and that the 13-subunit of Na,K-ATPase play a crucial role in these functions. In this proposal, we shall test the hypothesis that like E-cadherin, the b-subunit of Na,K-ATPase functions as a cell adhesion molecule to regulate epithelial polarity and to suppress invasion and motility of carcinoma cells. We shall assess whether b-subunit expression in renal clear-cell carcinoma cell lines reduces their invasiveness and tumorigenicity by both in vitro and in vivo assays. These studies will ultimately elucidate novel roles of the b-subunit of Na,K-ATPase in normal and disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK056216-03S1
Application #
6869244
Study Section
Pathology B Study Section (PTHB)
Program Officer
Ketchum, Christian J
Project Start
2001-04-15
Project End
2005-02-28
Budget Start
2003-04-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2004
Total Cost
$8,793
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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