Repression of Na,K-ATPase beta1-subunit by the transcription factor snail in carcinoma.
The Na,K-ATPase consists of two essential alpha- and beta-subunits and regulates the intracellular Na+ and K+ homeostasis. Although the alpha-subunit contains the catalytic activity, it is not active without functional beta-subunit. Here, we report that poorly differentiated carcinoma cell lines derived from colon, breast, kidney, and pancreas show reduced expression of the Na,K-ATPase beta1-subunit. Decreased expression of beta1-subunit in poorly differentiated carcinoma cell lines correlated with increased expression of the transcription factor Snail known to down-regulate E-cadherin. Ectopic expression of Snail in well-differentiated epithelial cell lines reduced the protein levels of E-cadherin and beta1-subunit and induced a mesenchymal phenotype. Reduction of Snail expression in a poorly differentiated carcinoma cell line by RNA interference increased the levels of Na,K-ATPase beta1-subunit. Furthermore, Snail binds to a noncanonical E-box in the Na,K-ATPase beta1-subunit promoter and suppresses its promoter activity. These results suggest that down-regulation of Na,K-ATPase beta1-subunit and E-cadherin by Snail are associated with events leading to epithelial to mesenchymal transition.
Espineda
Cromwell E
CE
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
Chang
Jay H
JH
Twiss
Jeffery
J
Rajasekaran
Sigrid A
SA
Rajasekaran
Ayyappan K
AK
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology*; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004285:Dogs; D015536:Down-Regulation / Q000235:genetics*; D024721:E-Box Elements / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D015820:Cadherins; D004268:DNA-Binding Proteins; D021122:Protein Subunits; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000254:Sodium-Potassium-Exchanging ATPase