Transforming growth factor-beta response elements of the skeletal alpha-actin gene. Combinatorial action of serum response factor, YY1, and the SV40 enhancer-binding protein, TEF-1.
Skeletal alpha-actin (SkA) is representative of the cardiac genes that are expressed at high levels in embryonic myocardium, down-regulated after birth, and reactivated by trophic signals including type beta-transforming growth factors (TGF beta). To investigate the molecular basis for cardiac-restricted and TGF beta-induced SkA transcription, we have undertaken a mutational analysis of the SkA promoter in ventricular myocytes, with emphasis on the role of three nominal serum response elements. Serum response factor (SRF) and the bifunctional factor YY1 are the predominant cardiac proteins contacting the proximal SRE (SRE1). Mutations of SRE1 that prevent recognition by SRF and YY1, or SRF alone, virtually abolish SkA transcription in both TGF beta- and vehicle-treated cells; mutation of distal SREs was ineffective. A mutation which selectively abrogates YY1 binding increases both basal and TGF beta-dependent expression, substantiating the predicted role of YY1 as an inhibitor of SRF effects. However, efficient SkA transcription requires combinatorial action of SRE1 with consensus sites for Sp1 and the SV40 enhancer-binding protein, TEF-1. As isolated motifs, either SRE1- or TEF-1-binding sites function as TGF beta response elements. Induction of the SkA promoter by TGF beta required SRF and TEF-1 in concert, unlike other pathways for TGF beta-dependent gene expression.
MacLellan
W R
WR
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
Lee
T C
TC
Schwartz
R J
RJ
Schneider
M D
MD
D000199:Actins / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002645:Chickens; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D050981:Erythroid-Specific DNA-Binding Factors; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D051381:Rats; D013539:Simian virus 40 / Q000378:metabolism; D016385:TATA Box; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D050986:YY1 Transcription Factor; D016335:Zinc Fingers
D000199:Actins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D050986:YY1 Transcription Factor; C494700:Yy1 protein, rat