Transcription factor RTEF-1 mediates α1-adrenergic reactivation of the fetal gene program in cardiac myocytes

alpha(1)-Adrenergic receptor stimulation induces cardiac myocytes to hypertrophy and reactivates many fetal genes, including beta-myosin heavy chain (beta MyHC) and skeletal alpha-actin (SKA), by signaling through myocyte-specific CAT (M-CAT) cis elements, binding sites of the transcriptional enhancer factor-1 (TEF-1) family of transcription factors. To examine functional differences between TEF-1 and related to TEF-1 (RTEF-1) in alpha(1)-adrenergic reactivation of the fetal program, expression constructs were cotransfected with beta MyHC and SKA promoter/reporter constructs in neonatal rat cardiac myocytes. TEF-1 overexpression tended to transactivate a minimal beta MyHC promoter but significantly interfered with a minimal SKA promoter. In contrast, RTEF-1 transactivated both the minimal beta MyHC and SKA promoters. TEF-1 and RTEF-1 also affected the alpha(1)-adrenergic response of the beta MyHC and SKA promoters differently. TEF-1 had no effect. In contrast, RTEF-1 potentiated the alpha(1)-adrenergic responses of the SKA promoter and of a -3.3-kb beta MyHC promoter. To determine why the promoters responded differently to TEF-1 and RTEF-1, promoters with mutated M-CAT elements were tested in the same way. The beta MyHC promoter required an intact M-CAT element to respond to TEF-1 and RTEF-1, whereas the SKA promoter M-CAT was required for the TEF-1 response but not for the RTEF-1 response, suggesting that SKA promoter-specific cofactors may be involved. By competition gel shift assay, the M-CAT of the minimal beta MyHC promoter had a lower affinity than that of the SKA promoter, which partly explains the different responses of these promoters to TEF1. These results highlight functional differences between TEF-1 and RTEF-1 and suggest a novel function of RTEF-1 in mediating the alpha(1)-adrenergic response in hypertrophic cardiac myocytes.