Transcription factor RTEF-1 mediates alpha1-adrenergic reactivation of the fetal gene program in cardiac myocytes.
Alpha1-adrenergic receptor stimulation induces cardiac myocytes to hypertrophy and reactivates many fetal genes, including beta-myosin heavy chain (betaMyHC) 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 alpha1-adrenergic reactivation of the fetal program, expression constructs were cotransfected with betaMyHC and SKA promoter/reporter constructs in neonatal rat cardiac myocytes. TEF-I overexpression tended to transactivate a minimal betaMyHC promoter but significantly interfered with a minimal SKA promoter. In contrast, RTEF-1 transactivated both the minimal betaMyHC and SKA promoters. TEF-1 and RTEF-I also affected the alpha1-adrenergic response of the betaMyHC and SKA promoters differently. TEF-1 had no effect. In contrast, RTEF-1 potentiated the alpha1-adrenergic responses of the SKA promoter and of a -3.3-kb betaMyHC 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 betaMyHC 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 betaMyHC 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 alpha1-adrenergic response in hypertrophic cardiac myocytes.
Department of Medicine, University of Pittsburgh, PA 15213, USA. als6+@pitt.edu
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Stewart
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Suzow
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Kubota
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Ueyama
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Chen
D000199:Actins / Q000235:genetics; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005333:Fetus / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D009124:Muscle Proteins / Q000378:metabolism / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000166:cytology*; D018995:Myosin Heavy Chains / Q000235:genetics; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D000091262:TEA Domain Transcription Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D000199:Actins; D000316:Adrenergic alpha-Agonists; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D011942:Receptors, Adrenergic, alpha; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; C486309:TEAD4 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D015500:Chloramphenicol O-Acetyltransferase; D018995:Myosin Heavy Chains