TRANSCRIPTION OF THE RAT SARCOPLASMIC-RETICULUM CA2-TRIPHOSPHATASE GENE IS INCREASED BY 3,5,3'-TRIIODOTHYRONINE RECEPTOR ISOFORM-SPECIFIC INTERACTIONS WITH THE MYOCYTE-SPECIFIC ENHANCER FACTOR-2A( ADENOSINE)

Thyroid hormone (T-3) increases the transcription of the sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) gene (SERCA 2) throug h three thyroid hormone response elements. The existence of repetitive cis elements with different configurations is likely to serve specifi c functions such as interactions with nuclear transcription factors. I n addition, the presence of different T-3 receptor isoforms (T(3)Rs) m ay contribute to another level of complexity in providing specificity for T-3 action. In this study, we investigated T(3)R alpha 1- vs. T(3) R beta 1-specific interactions with the myocyte enhancer-specific fact or-2 (MEF-2) on the expression of the SERCA 2 gene in transient transf ection assays in embryonal heart-derived H9c2 cells. MEF-2a in combina tion with either T(3)R alpha 1 or T(3)R beta 1 isoforms resulted in a 2.5-fold increase in SERCA 2 transgene expression in the absence of T- 3. Addition of T-3 did not induce any further increase in SERCA 2 expr ession when T(3)R alpha 1 and MEF-2 alpha expression vectors were cotr ansfected. In contrast, in the presence of T(3)R beta 1 and MEF-2, the addition of T-3 increased chlorampenicol acetyltransferase activity b y an additional 2.2-fold to a total 5.5-fold increase. The interaction between MEF-2a and T(3)R is transcription factor specific because ano ther factor that binds to MEF-2 consensus sites (heart factor 1b) was not able to interact with T(3)R. In addition, MEF-2a failed to interac t with other nuclear factors (cAMP response element-binding protein an d Egr-1) that stimulate SERCA 2 gene transcription. In addition, we fo und that a single homologous thyroid hormone response element is not a ble to mediate the interactions between MEF-2a and T(3)Rs to increase SERCA 2 gene transcription. Our findings point to T(3)R isoform-specif ic interactions with a cell type-specific transcription factor (MEF-2) in the regulation of SERCA 2 gene expression.