title: Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene.
abstract: The expression of cardiac hormones, atrial natriuretic peptide and B-type natriuretic peptide, is induced by cardiac wall stretch and responds to various hypertrophic agonists such as endothelin-1. In cardiac myocytes, endothelin-1 induces GATA-4 binding to the B-type natriuretic peptide gene, but the signaling pathways involved in endothelin-1-induced GATA-4 activation are unknown. Mitogen-activated protein kinase pathways are stimulated in response to various extracellular stimuli, and they modulate the function of several transcription activators. Here we show that inhibition of p38 kinase with SB203580 inhibited endothelin-1-induced GATA-4 binding to B-type natriuretic peptide gene and serine phosphorylation of GATA-4. Inhibition of extracellular signal-regulated protein kinase with MEK1 inhibitor PD98059 reduced basal and p38-induced GATA-4 binding activity, but it had no significant effect on endothelin-1-induced GATA-4 binding activity. Overexpression of p38 kinase pathway, but not extracellular signal-regulated kinase or c-Jun N-terminal protein kinase, activated GATA-4 binding to B-type natriuretic peptide gene and induced rat B-type natriuretic peptide promoter activity via proximal GATA binding sites. In conclusion, these findings demonstrate that activation of p38 kinase is necessary for hypertrophic agonist-induced GATA-4 binding to B-type natriuretic peptide gene and sufficient for GATA-dependent B-type natriuretic peptide gene expression.
authors.affiliation: Department of Pharmacology, Biocenter Oulu, P. O. Box 5000, University of Oulu, 90014 Oulu, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
authors.forename: Sampsa
authors.initials: S
authors.lastname: Pikkarainen
authors.forename: Theresa
authors.initials: T
authors.lastname: Majalahti-Palviainen
authors.forename: Heikki
authors.initials: H
authors.lastname: Tokola
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis* / Q000235:genetics; D001665:Binding Sites; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D050991:GATA4 Transcription Factor; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D020097:Natriuretic Peptide, Brain; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D050991:GATA4 Transcription Factor; D007093:Imidazoles; D011725:Pyridines; D014157:Transcription Factors; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one