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J Biol Chem, Vol. 274, Issue 31, 21544-21554, July 30, 1999
-Subunit Is Regulated by Antagonistic Effects between
Glucocorticoid Hormone and Ras Pathways in Salivary Epithelial
Cells
,,,¶
**, and§§
From the Departments of 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
Molecular Pharmacology and
Toxicology, ¶ Medicine, Physiology and Biophysics, and
** Biomedical Engineering, Will Rogers
Institute Pulmonary Research Center, and
§§ Center for Craniofacial Molecular Biology,
University of Southern California, Los Angeles, California 90089
-subunit expression, little is known about the molecular mechanisms
by which cells modulate -ENaC gene expression.
Previously, we have shown that salivary -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 -ENaC
expression is regulated in salivary epithelial Pa-4 cells. A region
located between 
1.5 and 1.0 kilobase pairs of the
-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 identified
-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 -ENaC expression
through the identified GRE. In summary, this study presents a mechanism
by which -ENaC expression is regulated in salivary
epithelial cells.
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