title: c-Src activation plays a role in endothelin-dependent hypertrophy of the cardiac myocyte.
abstract: Activation of the atrial natriuretic peptide (ANP) gene is regarded as one of the earliest and most reliable markers of hypertrophy in the ventricular cardiac myocyte. We have examined the role of the nonreceptor tyrosine kinases in the signaling mechanism(s) leading to hypertrophy using human ANP gene promoter activity as a marker. Endothelin (ET), a well known hypertrophic agonist, increased activity of c-Src, c-Yes, and Fyn within minutes and promoted a selective redistribution of each of these kinases within the cell. Overexpression of c-Src effected a significant increase in activity of a cotransfected human ANP promoter-driven chloramphenicol acetyl transferase reporter, while expression of either c-Yes or Fyn was considerably less effective in this regard. ET-dependent stimulation of the human ANP gene promoter was partially inhibited by co-transfection with dominant negative Ras or dominant negative Src or Csk or by treatment with the potent Src family-selective tyrosine kinase inhibitor PP1, suggesting that the Src family kinases are involved in signaling ET-dependent activation of this promoter. Both ET- and Src-dependent activation of the ANP promoter required the presence of a CArG motif in a serum response element-like structure between -422 and -413 but did not appear to require assembly of a ternary complex for full activity. These findings support a role for Src in the activation of ANP gene expression and suggest that this kinase may contribute in an important way to the signaling mechanisms that activate hypertrophy in the cardiac myocyte.
authors.affiliation: Metabolic Research Unit and Departments of Medicine, University of California, San Francisco, California 94143, USA. branka@itsa.ucsf.edu
authors.forename: B
authors.initials: B
authors.lastname: Kovacic
authors.forename: D
authors.initials: D
authors.lastname: Ilić
authors.forename: C H
authors.initials: CH
authors.lastname: Damsky
authors.forename: D G
authors.initials: DG
authors.lastname: Gardner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis* / Q000235:genetics; D001692:Biological Transport; D000081247:CSK Tyrosine-Protein Kinase; D006332:Cardiomegaly / Q000378:metabolism*; D002451:Cell Compartmentation; D002478:Cells, Cultured; D016232:Endothelins / Q000378:metabolism*; D006801:Humans; D009206:Myocardium / Q000166:cytology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051381:Rats; D017466:Receptors, Endothelin / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016232:Endothelins; D011518:Proto-Oncogene Proteins; D017466:Receptors, Endothelin; D009320:Atrial Natriuretic Factor; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C494957:FYN protein, human; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; C000631346:CSK protein, human; D010749:Phosphoprotein Phosphatases; D018631:ras Proteins