Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression.

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.

[1]  S. Reddy,et al.  Role and regulation of activator protein-1 in toxicant-induced responses of the lung. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[2]  Paul Shapiro,et al.  JNK1 and AP-1 regulate PMA-inducible squamous differentiation marker expression in Clara-like H441 cells. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[3]  N. Colburn,et al.  Transactivation of Fra-1 and Consequent Activation of AP-1 Occur Extracellular Signal-Regulated Kinase Dependently , 2002, Molecular and Cellular Biology.

[4]  P. Vacek,et al.  Different accumulation of activated extracellular signal-regulated kinases (ERK 1/2) and role in cell-cycle alterations by epidermal growth factor, hydrogen peroxide, or asbestos in pulmonary epithelial cells. , 2001, American journal of respiratory cell and molecular biology.

[5]  J. Bravman,et al.  Silica-induced activation of c-Jun-NH2-terminal amino kinases, protracted expression of the activator protein-1 proto-oncogene, fra-1, and S-phase alterations are mediated via oxidative stress. , 2001, Cancer research.

[6]  K. Rundell,et al.  The role of the SV40 ST antigen in cell growth promotion and transformation. , 2001, Seminars in cancer biology.

[7]  H. Pass,et al.  Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  V. Berezin,et al.  Fra-1 Induces Morphological Transformation and Increases In Vitro Invasiveness and Motility of Epithelioid Adenocarcinoma Cells , 1998, Molecular and Cellular Biology.

[9]  G. Viglietto,et al.  Neoplastic transformation of rat thyroid cells requires the junB and fra‐1 gene induction which is dependent on the HMGI‐C gene product , 1997, The EMBO journal.

[10]  M. Yaniv,et al.  Transformation by ras modifies AP1 composition and activity , 1997, Oncogene.

[11]  B. Mossman,et al.  Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. , 1996, Cancer research.

[12]  B. Mossman,et al.  Asbestos induces nuclear factor kappa B (NF-kappa B) DNA-binding activity and NF-kappa B-dependent gene expression in tracheal epithelial cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Busslinger,et al.  Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron , 1995, Molecular and cellular biology.

[14]  B. Mossman,et al.  Transcriptional activation of the proto-oncogene c-jun by asbestos and H2O2 is directly related to increased proliferation and transformation of tracheal epithelial cells. , 1995, Cancer research.

[15]  I. Verma,et al.  Transformation by Fos proteins requires a C-terminal transactivation domain , 1993, Molecular and cellular biology.

[16]  N. Heintz,et al.  Persistent induction of c-fos and c-jun expression by asbestos. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Bravo,et al.  The jun and fos protein families are both required for cell cycle progression in fibroblasts , 1991, Molecular and cellular biology.

[18]  A. Seaton,et al.  Asbestos: scientific developments and implications for public policy. , 1990, Science.

[19]  Bisharah Libbus,et al.  Characteristics of tumors and tumor cells cultured from experimental asbestos-induced mesotheliomas in rats. , 1987, The American journal of pathology.