title: Endogenous mono-ADP-ribosylation mediates smooth muscle cell proliferation and migration via protein kinase N-dependent induction of c-fos expression.
abstract: ADP-ribosylation has been coupled to intracellular events associated with smooth muscle cell vasoreactivity, cytoskeletal integrity and free radical damage. Additionally, there is evidence that ADP-ribosylation is required for smooth muscle cell proliferation. Our investigation employed selective inhibitors to establish that mono-ADP-ribosylation and not poly(ADP-ribosyl)ation was necessary for the stimulation of DNA synthesis by mitogens. Mitogen treatment increased concomitantly the activity of both soluble and particulate mono-ADP-ribosyltransferase, as well as the number of modified proteins. Inclusion of meta-iodobenzylguanidine (MIBG), a selective decoy substrate of arginine-dependent mono-ADP-ribosylation, prevented the modification of these proteins. MIBG also blocked the stimulation of DNA and RNA synthesis, prevented smooth muscle cell migration and suppressed the induction of c-fos and c-myc gene expression. An examination of relevant signal transduction pathways showed that MIBG did not interfere with MAP kinase and phosphatidylinositol 3-kinase stimulation; however, it did inhibit phosphorylation of the Rho effector, PRK1/2. This novel observation suggests that mono-ADP-ribosylation participates in a Rho- dependent signalling pathway that is required for immediate early gene expression.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre and Department of Physiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Yau
authors.forename: Brenda
authors.initials: B
authors.lastname: Litchie
authors.forename: Shawn
authors.initials: S
authors.lastname: Thomas
authors.forename: Benjamin
authors.initials: B
authors.lastname: Storie
authors.forename: Natalia
authors.initials: N
authors.lastname: Yurkova
authors.forename: Peter
authors.initials: P
authors.lastname: Zahradka
mesh_terms: D019797:3-Iodobenzylguanidine / Q000494:pharmacology; D036002:ADP Ribose Transferases / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D000804:Angiotensin II; C068870:3,4-dihydro-5-methyl-1(2H)-isoquinolinone; D000246:Adenosine Diphosphate Ribose; D019797:3-Iodobenzylguanidine; D004247:DNA; D036002:ADP Ribose Transferases; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; C061570:protein kinase N; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone