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Glucocorticoids Control ß-Catenin Protein Expression and Localization through Distinct Pathways that Can Be Uncoupled by Disruption of Signaling Events Required for Tight Junction Formation in Rat Mammary Epithelial Tumor Cells

Department of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, California 94720-3200

Address all correspondence and requests for reprints to: Gary L. Firestone, Department of Molecular and Cell Biology, 591 LSA, University of California at Berkeley, Berkeley, California 94720-3200. E-mail: glfire{at}uclink4.berkeley.edu.

In Con8 rat mammary epithelial tumor cells, the synthetic glucocorticoid dexamethasone stimulates the remodeling of tight junctions and adherens junctions before formation of highly sealed tight junctions. In this study, the expression and localization of key components of the apical junction were examined as potential targets of glucocorticoid signaling. Western blot and RT-PCR demonstrated that dexamethasone up-regulated ß-catenin protein and transcript expression and nearly ablated ß-catenin phosphorylation under conditions that led to a significant increase in monolayer transepithelial resistance. Indirect immunofluorescence revealed that dexamethasone treatment also caused ß-catenin to localize predominantly at the cell membrane rather than the nucleus. The glucocorticoid regulation of ß-catenin expression and localization was not a consequence of dexamethasone inhibition of cell growth, because both responses were unaltered in the presence of hydroxyurea. The steroid induction of ß-catenin expression and localization can be uncoupled by altering the function of signaling pathways needed for tight junction formation. Expression of dominant-negative RasN17 abolished dexamethasone up-regulation of ß-catenin protein expression without affecting its localization at the membrane. In contrast, exogenous treatment or constitutive production of TGF abolished the dexamethasone-induced alteration of ß-catenin localization without affecting the dexamethasone stimulation of ß-catenin expression. Taken together, our results demonstrate that glucocorticoids control ß-catenin at two distinct levels of cellular regulation that differ in their cell signaling requirements for the glucocorticoid regulation of mammary epithelial junctional dynamics.

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Ligands:   Dexamethasone  |  RU486

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