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J. Biol. Chem., Vol. 280, Issue 28, 26113-26120, July 15, 2005

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Nuclear Factor of Activated T Cells and Serum Response Factor Cooperatively Regulate the Activity of an -Actin Intronic Enhancer^*

Laura V. Gonzalez Bosc, Jeff J. Layne, Mark T. Nelson, and David C. Hill-Eubanks

From the Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont 05405

Expression of -actin in smooth muscle cells (SMCs) is regulated, in part, by an intronic serum response factor (SRF)-binding CArG element. We have identified a conserved nuclear factor of activated T cells (NFAT) binding site that overlaps this CArG box and tested the hypothesis that this site plays a previously unrecognized role in regulating -actin expression. A reporter construct prepared using a 56-bp region of the mouse -actin first intron containing SRF, NFAT, and AP-1 sites (SNAP) acted as an enhancer element in the context of a minimal thymidine kinase promoter. Basal reporter activity following expression in SMCs was robust and sensitive to the calcineurin-NFAT pathway inhibitors cyclosporin A and FK506. Mutating either the NFAT or SRF binding site essentially abolished reporter activity, suggesting that both NFAT and SRF binding are required. Basal activity in non-smooth muscle HEK293 cells was SRF-dependent but NFAT-independent and 8-fold lower than that in SMCs. Activation of NFAT in HEK293 cells induced an 4-fold increase in activity that was dependent on the integrity of both NFAT and SRF binding sites. NFATc3·SRF complex formation, demonstrated by co-immunoprecipitation, was facilitated by the presence of SNAP oligonucleotide. Inhibition of the calcineurin-NFAT pathway decreased -actin expression in cultured SMCs, suggesting that the molecular interaction of NFAT and SRF at SNAP may be physiologically relevant. These data provide the first evidence that NFAT and SRF may interact to cooperatively regulate SMC-specific gene expression and support a role for NFAT in the phenotypic maintenance of smooth muscle.

Received for publication, October 21, 2004 , and in revised form, April 15, 2005.

^* This work was supported by National Institutes of Health Grants HL44455, HL63722, DDK065947, and DDK53832(to M. T. N.); a post-doctoral fellowship from the American Heart Association (to L. V. G. B.); National Institutes of Health Training Grant HL07944 (to J. J. L.); and a grant from the Totman Trust for Medical Research. 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Pharmacology, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405. Tel.: 802-656-2500; Fax: 802-656-4523; E-mail: David.Hill-Eubanks{at}uvm.edu.

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