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J. Biol. Chem., Vol. 283, Issue 20, 14012-14021, May 16, 2008

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Coordination of Growth and Endoplasmic Reticulum Stress Signaling by Regulator of Calcineurin 1 (RCAN1), a Novel ATF6-inducible Gene^*

From the San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, California 92182

Exposing cells to conditions that modulate growth can impair endoplasmic reticulum (ER) protein folding, leading to ER stress and activation of the transcription factor, ATF6. ATF6 binds to ER stress response elements in target genes, inducing expression of proteins that enhance the ER protein folding capacity, which helps overcome the stress and foster survival. To examine the mechanism of ATF6-mediated survival in vivo, we developed a transgenic mouse model that expresses a novel conditionally activated form of ATF6. We previously showed that activating ATF6 protected the hearts of ATF6 transgenic mice from ER stresses. In the present study, transcript profiling identified modulatory calcineurin interacting protein-1 (MCIP1), also known as regulator of calcineurin 1 (RCAN1), as a novel ATF6-inducible gene that encodes a known regulator of calcineurin/nuclear factor of activated T cells (NFAT)-mediated growth and development in many tissues. The ability of ATF6 to induce RCAN1 in vivo was replicated in cultured cardiac myocytes, where adenoviral (AdV)-mediated overexpression of activated ATF6 induced the RCAN1 promoter, up-regulated RCAN1 mRNA, inhibited calcineurin phosphatase activity, and exerted a striking growth modulating effect that was inhibited by RCAN1-targeted small interfering RNA. These results demonstrate that RCAN1 is a novel ATF6 target gene that may coordinate growth and ER stress signaling pathways. By modulating growth, RCAN1 may reduce the need for ER protein folding, thus helping to overcome the stress and enhance survival. Moreover, these results suggest that RCAN1 may also be a novel integrator of growth and ER stress signaling in many other tissues that depend on calcineurin/NFAT signaling for optimal growth and development.

Received for publication, November 29, 2007 , and in revised form, February 15, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL-075573 and HL-085577. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ Fellows of the Rees-Stealy Research Foundation and the San Diego State University Heart Institute.

² Scholar of the San Diego Chapter of the Achievement Rewards for College Scientists (ARCS) Foundation.

³ To whom correspondence should be addressed: 5500 Campanile Dr., San Diego, CA 92182. Tel.: 619-594-2959; Fax: 619-594-5676; E-mail: cglembotski{at}sciences.sdsu.edu.