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  • Title: Role for early growth response-1 protein in alpha(1)-adrenergic stimulation of fibroblast growth factor-2 promoter activity in cardiac myocytes.
    Author: Jin Y, Sheikh F, Detillieux KA, Cattini PA.
    Journal: Mol Pharmacol; 2000 May; 57(5):984-90. PubMed ID: 10779383.
    Abstract:
    Fibroblast growth factor-2 (FGF-2), a mitogenic, angiogenic, and cardioprotective agent, is released from the postnatal heart by a mechanism of transient remodelling of the sarcolemma during contraction. Both release of FGF-2 and its synthesis can be increased with adrenergic stimulation. We reported previously that FGF-2 synthesis can be regulated at the transcriptional level by alpha-adrenergic stimulation of cultured neonatal rat cardiac myocytes as well as in the adult mouse heart. Examination of the proximal promoter region of both human and rat FGF-2 gene sequences revealed binding sites for the early growth response-1 (Egr-1) protein. Using gel mobility shift assays, we observed a transient increase in a complex between nuclear extracts from neonatal rat cardiac myocytes treated with inducers of Egr-1, including the alpha-adrenergic agonist phenylephrine, angiotensin II, and phorbol ester, and a consensus Egr-1 DNA element. A similar complex was seen with the FGF-2 promoter region -7/+42 as the DNA probe, but not when the Egr-1 element at nucleotides +3/+31 was disrupted. Participation of Egr-1 protein in the complex was confirmed by competition with Egr-1 DNA elements and antibodies. With deletion analysis and transfection of neonatal rat cardiac myocytes, the alpha-adrenergic response was localized to nucleotides -110/+42 of the FGF-2 gene in the context of a hybrid FGF-2/luciferase reporter gene, -110FGFp.luc. Overexpression of Egr-1 increased -110FGFp.luc gene expression, whereas mutation of its Egr-1 element at nucleotides +3/+31 abolished alpha-adrenergic responsiveness. These data indicate that Egr-1 is involved in the alpha-adrenergic stimulation of the FGF-2 promoter region in neonatal cardiac myocytes.
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