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-2a

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Abstract
Thyroid hormone (T3) increases the transcription of the sarcoplas- micreticulumCa21adenosinetriphosphatase(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 transcrip- tion factors. In addition, the presence of different T3receptor isoforms (T3Rs) may contribute to another level of complexity in providing specificity for T3 action. In this study, we investigated T3Ra1- vs. T3Rb1-specific interactions with the myocyte enhancer-specific fac- tor-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 T3Ra 1o r T 3 R b1 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 expressionwhenT3Ra1andMEF-2aexpressionvectorswerecotrans- fected. In contrast, in the presence of T3Rb1 and MEF-2, the addition of T3 increased chlorampenicol acetyltransferase activity by an ad- ditional 2.2-fold to a total 5.5-fold increase. The interaction between MEF-2a and T3R is transcription factor specific because another fac- tor 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 in- crease SERCA 2 gene transcription. Our findings point to T3R iso- form-specific interactions with a cell type-specific transcription factor (MEF-2) in the regulation of SERCA 2 gene expression. (Endo- crinology 138: 26-32, 1997)