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J. Biol. Chem., Vol. 283, Issue 5, 2554-2563, February 1, 2008

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Activator Protein-1 Contributes to High NaCl-induced Increase in Tonicity-responsive Enhancer/Osmotic Response Element-binding Protein Transactivating Activity^*

Carlos E. Irarrazabal, Chester K. Williams, Megan A. Ely, Michael J. Birrer, Arlyn Garcia-Perez, Maurice B. Burg, and Joan D. Ferraris¹

From the Laboratory of Kidney and Electrolyte Metabolism, NHLBI, and Cell and Cancer Biology Branch, NCI, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892

Tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP) is a Rel protein that activates transcription of osmoprotective genes at high extracellular NaCl. Other Rel proteins NFAT1–4 and NF-B complex with activator protein-1 (AP-1) to transactivate target genes through interaction at composite NFAT/NF-B·AP-1 sites. TonEBP/OREBP target genes commonly have one or more conserved AP-1 binding sites near TonEBP/OREBP cognate elements (OREs). Also, TonEBP/OREBP and the AP-1 proteins c-Fos and c-Jun are all activated by high NaCl. We now find, using an ORE·AP-1 reporter from the target aldose reductase gene or the same reporter with a mutated AP-1 site, that upon stimulation by high extracellular NaCl, 1) the presence of a wild type, but not a mutated, AP-1 site contributes to TonEBP/OREBP-dependent transcription and 2) AP-1 dominant negative constructs inhibit TonEBP/OREBP-dependent transcription provided the AP-1 site is not mutated. Using supershifts and an ORE·AP-1 probe, we find c-Fos and c-Jun present in combination with TonEBP/OREBP. Also, c-Fos and c-Jun coimmunoprecipitate with TonEBP/OREBP, indicating physical association. Small interfering RNA knockdown of either c-Fos or c-Jun inhibits high NaCl-induced increase of mRNA abundance of the TonEBP/OREBP target genes AR and BGT1. Furthermore, a dominant negative AP-1 also reduces high NaCl-induced increase of TonEBP/OREBP transactivating activity. Inhibition of p38, which is known to stimulate TonEBP/OREBP transcriptional activity, reduces high NaCl-dependent transcription of an ORE·AP-1 reporter only if the AP-1 site is intact. Thus, AP-1 is part of the TonEBP/OREBP enhanceosome, and its role in high NaCl-induced activation of TonEBP/OREBP may require p38 activity.

Received for publication, April 26, 2007 , and in revised form, November 28, 2007.

^* This research was supported by the Intramural Research Program of the NHLBI, National Institutes of Health. 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.

¹ To whom correspondence should be addressed: Laboratory of Kidney and Electrolyte Metabolism, NHLBI, National Institutes of Health, 10 Center Dr.-MSC 1603, Bethesda, MD 20892-1603; Tel.: 301-496-1559; Fax: 301-402-1443; E-mail: ferraris{at}nhlbi.nih.gov.

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