title: Poly(ADP-ribose) polymerase-1 regulates activation of activator protein-1 in murine fibroblasts.
abstract: Poly(ADP-ribose) polymerase (PARP)-1 is activated in response to DNA injury in the nucleus of eukaryotic cells and has been implicated in cell dysfunction in inflammation. We investigated the role of PARP-1 on the AP-1 pathway, which is involved in the signal transduction of the inflammatory process. In murine wild-type fibroblasts, oxidative challenge by peroxynitrite and hydrogen peroxide or immunological challenge by IL-1 and 20% FCS induced phosphorylation of the mitogen-activated protein kinase kinase-4, activation of c-Jun N-terminal kinase (JNK), and DNA binding of AP-1. In comparative experiments, peroxynitrite induced DNA binding of heat shock factor-1. Pretreatment of wild-type cells with 5-iodo-6-amino-1,2-benzopyrone, a PARP-1 inhibitor, inhibited JNK activation and DNA binding of AP-1. In parallel experiments in PARP-1-deficient fibroblasts, DNA binding of AP-1 was completely abolished. Activation of JNK was significantly elevated at basal condition, but it exhibited a lesser increase after oxidative or immunological challenge than in wild-type fibroblasts. Nuclear content of phosphorylated mitogen-activated protein kinase kinase-4 was observed in PARP-1-deficient cells after peroxynitrite challenge only. Western blotting analysis for AP-1 subunits indicated that c-Fos was similarly expressed in wild-type and PARP-1-deficient cells. Phosphorylated c-Jun was expressed after oxidative or immunological challenge, but not in basal condition, in wild-type cells; however, it was significantly elevated at basal condition and further enhanced after oxidative or immunological challenge in PARP-1-deficient cells. No DNA binding of heat shock factor-1 was observed in PARP-1-deficient cells. These data demonstrate that PARP-1 plays a pivotal role in the modulation of transcription.
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Andreone
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connor
authors.forename: Alvin
authors.initials: A
authors.lastname: Denenberg
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hake
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D007375:Interleukin-1 / Q000633:toxicity; D048031:JNK Mitogen-Activated Protein Kinases; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D030421:Peroxynitrous Acid / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D007375:Interleukin-1; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D030421:Peroxynitrous Acid; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; C482779:MAP3K4 protein, human; C482780:Map3k4 protein, mouse