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J. Biol. Chem., Vol. 279, Issue 40, 41750-41757, October 1, 2004

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Stress-induced Expression of the Subunit (FXYD2) Modulates Na,K-ATPase Activity and Cell Growth^*

Randall K. Wetzel, Jennifer L. Pascoa, and Elena Arystarkhova

From the Laboratory of Membrane Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

In kidney, the Na,K-ATPase is associated with a single span protein, the subunit (FXYD2). Two splice variants are differentially expressed along the nephron and have a differential influence on Na,K-ATPase when stably expressed in mammalian cells in culture. Here we used a combination of gene induction and gene silencing techniques to test the functional impact of by means other than transfection. NRK-52E cells (of proximal tubule origin) do not express as a protein under regular tissue culture conditions. However, when they were exposed to hyperosmotic medium, induction of only the a splice variant was observed, which was accompanied by a reduction in the rate of cell division. Kinetic analysis of stable enzyme properties from control (11) and hypertonicity-treated cultures (11a) revealed a significant reduction (up to 60%) of Na,K-ATPase activity measured under V_max conditions with little or no change in the amounts of 11. This effect as well as the reduction in cell growth rate was practically abolished when expression was knocked down using specific small interfering RNA duplexes. Surprisingly, a similar induction of endogenous a because of hypertonicity was seen in rat cell lines of other than renal origin: C6 (glioma), PC12 (pheochromocytoma), and L6 (myoblasts). Furthermore, exposure of NRK-52E cells to other stress inducers such as heat shock, exogenous oxidation, and chemical stress also resulted in a selective induction of a. Taken together, the data imply that induction of a may have adaptive value by being a part of a general cellular response to genotoxic stress.

Received for publication, May 20, 2004 , and in revised form, July 19, 2004.

^* This work was supported by grants from Harvard Medical School 50th Anniversary Scholars in Medicine, by a Margaret Walters and Daughters Fellowship in memory of Carl Walter, M.D.,'32 (to E. A.), and by Grant HL-36271 from the National Institutes of Health (to K. J. Sweadner). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Massachusetts General Hospital, Wellman 415, 55 Fruit St., Boston, MA 02114. Tel.: 617-726-0758; Fax: 617-726-7526; E-mail: aristarkhova{at}helix.mgh.harvard.edu.

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