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Endocrinology Vol. 138, No. 1 26-32
Copyright © 1997 by The Endocrine Society


ARTICLES

Transcription of the Rat Sarcoplasmic Reticulum Ca2+ Adenosine Triphosphatase Gene Is Increased by 3,5,3'-Triiodothyronine Receptor Isoform-Specific Interactions with the Myocyte-Specific Enhancer Factor-2a1

Anselmo S. Moriscot2, M. Richard Sayen, Ronald Hartong, Patricia Wu and Wolfgang H. Dillmann

Department of Medicine, Division of Endocrinology and Metabolism, University of California-San Diego, La Jolla, California 92093-0618; and the Department of Internal Medicine, University of Heidelberg (R.H.), Heidelberg, Germany

Thyroid hormone (T3) increases the transcription of the sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) gene (SERCA 2) through three thyroid hormone response elements. The existence of repetitive cis elements with different configurations is likely to serve specific functions such as interactions with nuclear transcription factors. In addition, the presence of different T3 receptor isoforms (T3Rs) may contribute to another level of complexity in providing specificity for T3 action. In this study, we investigated T3R{alpha}1- vs. T3Rß1-specific interactions with the myocyte enhancer-specific factor-2 (MEF-2) on the expression of the SERCA 2 gene in transient transfection assays in embryonal heart-derived H9c2 cells. MEF-2a in combination with either T3R{alpha}1 or T3Rß1 isoforms resulted in a 2.5-fold increase in SERCA 2 transgene expression in the absence of T3. Addition of T3 did not induce any further increase in SERCA 2 expression when T3R{alpha}1 and MEF-2a expression vectors were cotransfected. In contrast, in the presence of T3Rß1 and MEF-2, the addition of T3 increased chlorampenicol acetyltransferase activity by an additional 2.2-fold to a total 5.5-fold increase. The interaction between MEF-2a and T3R is transcription factor specific because another factor that binds to MEF-2 consensus sites (heart factor 1b) was not able to interact with T3R. In addition, MEF-2a failed to interact with other nuclear factors (cAMP response element-binding protein and Egr-1) that stimulate SERCA 2 gene transcription. In addition, we found that a single homologous thyroid hormone response element is not able to mediate the interactions between MEF-2a and T3Rs to increase SERCA 2 gene transcription. Our findings point to T3R isoform-specific interactions with a cell type-specific transcription factor (MEF-2) in the regulation of SERCA 2 gene expression.




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