Transcription Factor RTEF-1 Mediates ₁-Adrenergic Reactivation of the Fetal Gene Program in Cardiac Myocytes

From the Graduate Program in Biochemistry and Molecular Genetics (A.F.R.S.), the Division of Cardiology, Department of Medicine (A.F.R.S., J.S., T.K., T.U.), and the Department of Neurobiology (H.-H.C.), University of Pittsburgh, Pittsburgh, Pa.

Correspondence to Alexandre Stewart, PhD, Division of Cardiology, Department of Medicine, Biomedical Science Tower 1704.3, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA 15213. E-mail als6+{at}pitt.edu

Abstract—₁-Adrenergic receptor stimulation induces cardiac myocytes to hypertrophy and reactivates many fetal genes, including ß-myosin heavy chain (ßMyHC) and skeletal -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 ₁-adrenergic reactivation of the fetal program, expression constructs were cotransfected with ßMyHC and SKA promoter/reporter constructs in neonatal rat cardiac myocytes. TEF-1 overexpression tended to transactivate a minimal ßMyHC promoter but significantly interfered with a minimal SKA promoter. In contrast, RTEF-1 transactivated both the minimal ßMyHC and SKA promoters. TEF-1 and RTEF-1 also affected the ₁-adrenergic response of the ßMyHC and SKA promoters differently. TEF-1 had no effect. In contrast, RTEF-1 potentiated the ₁-adrenergic responses of the SKA promoter and of a -3.3-kb ßMyHC 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 ßMyHC 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 ßMyHC promoter had a lower affinity than that of the SKA promoter, which partly explains the different responses of these promoters to TEF-1. These results highlight functional differences between TEF-1 and RTEF-1 and suggest a novel function of RTEF-1 in mediating the ₁-adrenergic response in hypertrophic cardiac myocytes.

Key Words: cardiac myocyte • ₁-adrenergic stimulation • transcription factor • fetal gene

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