Environmental Health Perspectives 105, Supplement 5, September 1997: Article by Mossman et al.

Environmental Health Perspectives 105, Supplement 5, September 1997

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Cell Signaling Pathways Elicited by Asbestos

Brooke T. Mossman, ¹ Steven Faux, ¹ Yvonne Janssen, ¹ Luis A. Jimenez, ¹ Cynthia Timblin, ¹ Christine Zanella, ¹ Jonathan Goldberg, ¹ Eric Walsh, ¹ Aaron Barchowsky, ² and Kevin Driscoll ³

¹ Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont
² Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire
³ Procter and Gamble, Inc., Cincinnati, Ohio

Abstract
In recent years, it has become apparent that minerals can trigger alterations in gene expression by initiating signaling events upstream of gene transactivation. These cascades may be initiated at the cell surface after interaction of minerals with the plasma membrane either through receptorlike mechanisms or integrins. Alternatively, signaling pathways may be stimulated by active oxygen species generated both during phagocytosis of minerals and by redox reactions on the mineral surface. At least two signaling cascades linked to activation of transcription factors, i.e., DNA-binding proteins involved in modulating gene expression and DNA replication, are stimulated after exposure of lung cells to asbestos fibers in vitro. These include nuclear factor Kappa

B (NF

B) and the mitogen-activated protein kinase (MAPK) cascade important in regulation of the transcription factor, activator protein-1 (AP-1). Both NF Kappa

B and AP-1 bind to specific DNA sequences within the regulatory or promoter regions of genes that are critical to cell proliferation and inflammation. Unraveling the cell signaling cascades initiated by mineral dusts and pharmacologic inhibition of these events may be important for the control and treatment of mineral-associated occupational diseases. -- Environ Health Perspect 105(Suppl 5):1121-1125 (1997)

Key words : asbestos, gene expression, protein kinases, NF Kappa B, transcription factors

This paper is based on a presentation at The Sixth International Meeting on the Toxicology of Natural and Man-Made Fibrous and Non-Fibrous Particles held 15-18 September 1996 in Lake Placid, New York. Manuscript received at EHP 26 March 1997; accepted 7 May 1997.
The authors thank L. Sabens for preparation of this manuscript. This research was supported by grants from the National Institute of Environmental Health Sciences (ESO6499, ESO7038), National Heart, Lung and Blood Institute (HL39469), and National Institute for Occupational Safety and Health Special Emphasis Research Career Award.
Address correspondence to Dr. B.T. Mossman, Department of Pathology, University of Vermont College of Medicine, Soule Medical Alumni Building, Burlington, VT 05405. Telephone: (802) 656-0382. Fax: (802) 656-8892.
Abbreviations used: AOS, active oxygen species; AP-1, activator protein-1; BrdU, 5'-bromodeoxyuridine; EGFR, epidermal growth factor receptor; EMSA, electrophoretic mobility shift assays; ERK1, ERK2, extracellular signaling kinases; HTE, hamster tracheal epithelial; JNK1, JNK2, stress-related protein kinases; MAPK, mitogen-activated protein kinase(s); MAPK, MEKK kinase kinase; NAC, N-acetylcysteine; NF B, nuclear factor B; RLE, rat alveolar type II epithelial cells, RPM, rat pleural mesothelial; TNF- , tumor necrosis factor alpha; TPA, 12-O-tetradecanoylphorbol-13-acetate; UV, ultraviolet.

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Last Update: October 27, 1997