title: Role of activator protein-1 on the effect of arginine-glycine-aspartic acid containing peptides on transforming growth factor-beta1 promoter activity.
abstract: While arginine-glycine-aspartic acid-based peptidomimetics have been employed for the treatment of cardiovascular disorders and cancer, their use in other contexts remains to be explored. Arginine-glycine-aspartic acid-serine induces Transforming growth factor-beta1 transcription in human mesangial cells, but the molecular mechanisms involved have not been studied extensively. We explored whether this effect could be due to Activator protein-1 activation and studied the potential pathways involved. Addition of arginine-glycine-aspartic acid-serine promoted Activator protein-1 binding to its cognate sequence within the Transforming growth factor-beta1 promoter as well as c-jun and c-fos protein abundance. Moreover, this effect was suppressed by curcumin, a c-Jun N terminal kinase inhibitor, and was absent when the Activator protein-1 cis-regulatory element was deleted. Activator protein-1 binding was dependent on the activity of integrin linked kinase, as transfection with a dominant negative mutant suppressed both Activator protein-1 binding and c-jun and c-fos protein increment. Integrin linked kinase was, in turn, dependent on Phosphoinositol-3 kinase activity. Arginine-glycine-aspartic acid-serine stimulated Phosphoinositol-3 kinase activity, and Transforming growth factor-beta1 promoter activation was abrogated by the use of Phosphoinositol-3 kinase specific inhibitors. In summary, we propose that arginine-glycine-aspartic acid-serine activates Integrin linked kinase via the Phosphoinositol-3 kinase pathway and this leads to activation of c-jun and c-fos and increased Activator protein-1 binding and Transforming growth factor-beta1 promoter activity. These data may contribute to understand the molecular mechanisms involved in the cellular actions of arginine-glycine-aspartic acid-related peptides and enhance their relevance as these products evolve into clinical therapeutic use.
authors.affiliation: Nephrology Section and Research Unit, Hospital Príncipe de Asturias, Alcalá de Henares, Madrid, Spain. mpiedad.ruiz@uah.es
authors.forename: M P
authors.initials: MP
authors.lastname: Ruiz-Torres
authors.forename: G
authors.initials: G
authors.lastname: Perez-Rivero
authors.forename: M L
authors.initials: ML
authors.lastname: Diez-Marques
authors.forename: M
authors.initials: M
authors.lastname: Griera
authors.forename: R
authors.initials: R
authors.lastname: Ortega
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez-Puyol
authors.forename: D
authors.initials: D
authors.lastname: Rodríguez-Puyol
mesh_terms: D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D010456:Peptides, Cyclic; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; C507169:cyclic arginine-glycine-aspartic acid peptide; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases