Mechanisms of estrogen receptor action in the myocardium - Rapid gene activation via the ERK1/2 pathway and serum response elements

We have previously shown that the myocardium is a target tissue for estroge n. Here, we have identified rapid non-nuclear estrogen effects on the expre ssion of the early growth response gene-1 (Egr-1) in cardiomyocytes. Egr-1 mRNA and protein were rapidly and strongly induced by estrogen in an estrog en receptor-dependent manner via the extracellular signal-regulated kinase, ERK1/2. A promoter analysis study of a 1.2-kilobase Egr-1 promoter fragmen t revealed that the serum response elements (SREs) but not the estrogen res ponse elements or AP-1 sites are responsible for Egr-1 induction by estroge n, identifying a novel mechanism of estrogen receptor-dependent gene activa tion in the myocardium. Both estrogen receptor-alpha and -beta induced the Egr-1 promoter via the SREs as well as an artificial promoter consisting of only five SREs in cardiomyocytes. Electrophoretic mobility shift assays sh owed that a protein complex containing serum response factor or an antigeni cally related protein was recruited to the SREs by estrogen treatment of pr imary cardiomyocytes. The recruitment of the protein complex was inhibited by the specific estrogen receptor antagonist ICI 182,780 as well as the MEK inhibitor PD 98059. Taken together, these results identify SREs as importa nt promoter control elements for an estrogen receptor-dependent mechanism o f gene activation in the myocardium.