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Molecular and Cellular Biology, August 2005, p. 6649-6659, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6649-6659.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulation of Calcineurin through Transcriptional Induction of the calcineurin Aß Promoter In Vitro and In Vivo

Toru Oka, Yan-Shan Dai, and Jeffery D. Molkentin*

Department of Pediatrics, University of Cincinnati, and Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, Ohio

Received 21 December 2004/ Returned for modification 19 January 2005/ Accepted 4 May 2005

The calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway has been shown to be of critical importance in regulating the growth response of cardiac myocytes. We have previously demonstrated that calcineurin Aß (CnAß) mRNA and protein are increased in response to growth stimulation, although the precise regulatory mechanism underlying CnAß upregulation is not clear. Here, we isolated the mouse CnAß promoter and characterized its responsiveness to growth stimuli in vitro and in vivo. A 2.3-kb promoter fragment was strongly activated by phenylephrine and endothelin-1 stimulation and by cotransfection with constitutively active CnA, NFATc4, and GATA4. Using chromatin immunoprecipitation, sequence regions were identified within the 2.3-kb promoter that associated with NFAT and GATA4, as well as with acetylated histone H3, following agonist stimulation. Consistent with the chromatin immunoprecipitation experiments, deletion of the distal half of the CnAß promoter severely reduced NFAT, GATA4, and hypertrophic agonist-mediated activation. To investigate in vivo activity, we generated ß-galactosidase (LacZ) containing transgenic mice under the control of the CnAß 2.3-kb promoter. CnAß-LacZ mice showed expression in the heart that was cyclosporine sensitive, as well as expression in the central nervous system and skeletal muscle from early embryonic stages through adulthood. CnAß-LacZ mice were subjected to cardiac pressure overload stimulation and crossbreeding with mice containing cardiac-specific transgenes for activated calcineurin and NFATc4, which revealed inducible expression in the heart. These results indicate that the CnAß 2.3-kb promoter is specifically activated by hypertrophic stimuli through a positive feedback mechanism involving NFAT and GATA4 transcription factors, suggesting transcriptional induction of CnAß expression as an additional means of regulating calcineurin activity in the heart.

* Corresponding author. Mailing address: Cincinnati Children's Hospital Medical Center, Division of Molecular Cardiovascular Biology, 3333 Burnet Ave., MLC7020, Cincinnati OH 45229-3039. Phone: (513) 636-3557. Fax: (513) 636-5958. E-mail:Jeff.Molkentin{at}cchmc.org.

Molecular and Cellular Biology, August 2005, p. 6649-6659, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6649-6659.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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