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The Gene Expression of the Amiloride-sensitive Epithelial Sodium Channel α-Subunit Is Regulated by Antagonistic Effects between Glucocorticoid Hormone and Ras Pathways in Salivary Epithelial Cells*

H. H. Lin,Mark D. Zentner,Huei-Li Lily Ho,Kwang-Jin Kim,D. Ann

Published 1999 in Journal of Biological Chemistry

ABSTRACT

The functional expression of the amiloride-sensitive epithelial sodium channel (ENaC) in select epithelia is critical for maintaining electrolyte and fluid homeostasis. Although ENaC activity is strictly dependent upon its α-subunit expression, little is known about the molecular mechanisms by which cells modulate α-ENaC gene expression. Previously, we have shown that salivary α-ENaC expression is transcriptionally repressed by the activation of Raf/extracellular signal-regulated protein kinase pathway. Here, this work further investigates the molecular mechanism(s) by which α-ENaCexpression is regulated in salivary epithelial Pa-4 cells. A region located between −1.5 and −1.0 kilobase pairs of theα-ENaC 5′-flanking region is demonstrated to be indispensable for the maximal and Ras-repressible reporter expression. Deletional analyses using heterologous promoter constructs reveal that a DNA sequence between −1355 and −1269 base pairs functions as an enhancer conferring the high level of expression on reporter constructs, and this induction effect is inhibited by Ras pathway activation. Mutational analyses indicate that full induction and Ras-mediated repression require a glucocorticoid response element (GRE) located between −1323 and −1309 base pairs. The identifiedα-ENaC GRE encompassing sequence (−1334/−1306) is sufficient to confer glucocorticoid receptor/dexamethasone-dependent and Ras-repressible expression on both heterologous and homologous promoters. This report demon- strates for the first time that the cross-talk between glucocorticoid receptor and Ras/extracellular signal-regulated protein kinase signaling pathways results in an antagonistic effect at the transcriptional level to modulate α-ENaC expression through the identified GRE. In summary, this study presents a mechanism by which α-ENaC expression is regulated in salivary epithelial cells.

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