SERUM RESPONSE FACTOR MEDIATES AP-1-DEPENDENT INDUCTION OF THE SKELETAL ALPHA-ACTIN PROMOTER IN VENTRICULAR MYOCYTES

''Fetal'' gene transcription, including activation of the skeletal alp ha-actin (SkA) promoter, is provoked in cardiac myocytes by mechanical stress and trophic ligands. Induction of the promoter by transforming growth factor beta or norepinephrine requires serum response factor ( SRF) and TEF-1; expression is inhibited by YY1. We and others postulat ed that immediate-early transcription factors might couple trophic sig nals to this fetal program. However, multiple Fos/Jun proteins exist, and the exact relationship between control by Fos/Jun versus SRF, TEF- 1, and YY1 is unexplained. We therefore cotransfected ventricular myoc ytes with Fos, Jun, or JunB, and SkA reporter genes, SkA transcription was augmented by Jun, Fos/Jun, Fos/JunB, and Jun/JunB; Fos and JunB a lone were neutral or inhibitory. Mutation of the SRF site, SRE1, impai red activation by Jun; YY1, TEF-1, and Sp1 sites were dispensable. SRE 1 conferred Jun activation to a heterologous promoter, as did the c-fo s SRE. Deletions of DNA binding, dimerization, or trans-activation dom ains of Jun and SRF abolished activation by Jun and synergy with SRF. Neither direct binding of Fos/Jun to SREs, nor physical interaction be tween Fos/Jun and SRF, was detected in mobility-shift assays. Thus, AP -1 factors activate a hypertrophy-associated gene via SRF, without det ectable binding to the promoter or to SRF.