title: Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression.
abstract: Mesothelioma is a unique and insidious tumor associated historically with occupational exposure to asbestos. The transcription factor, activator protein-1 (AP-1) is a major target of asbestos-induced signaling pathways. Here, we demonstrate that asbestos-induced mesothelial cell transformation is linked to increases in AP-1 DNA binding complexes and the AP-1 component, Fra-1. AP-1 binding to DNA was increased dramatically in mesothelioma cell lines in comparison to isolated rat pleural mesothelial (RPM) cells. Elevated levels of AP-1 complexes, including significant increases in c-Jun, JunB and Fra-1, were found in asbestos-exposed RPM cells, but only Fra-1 expression was significantly increased and protracted in both asbestos-exposed RPM cells and mesothelioma cell lines. Asbestos-induced Fra-1 expression in RPM cells was dependent on stimulation of the extracellular signal-regulated kinases (ERKs 1/2). Inhibition of ERK phosphorylation or transfection with dominant-negative fra-1 constructs reversed the transformed phenotype of mesothelioma cells and anchorage-independent growth in soft agar. In summary, we demonstrate that ERK-dependent Fra-1 is elevated in AP-1 complexes in response to asbestos fibers and is critical to the transformation of mesothelial cells.
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington 05405, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ramos-Nino
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Timblin
authors.forename: Brooke T
authors.initials: BT
authors.lastname: Mossman
mesh_terms: D000818:Animals; D001194:Asbestos / Q000633:toxicity; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D004789:Enzyme Activation; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008654:Mesothelioma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D010994:Pleura / Q000166:cytology / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099169:Fos-Related Antigen 1
chemical_list: D001194:Asbestos; D004273:DNA, Neoplasm; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1