Abstract
Crocidolite asbestos elicits oxidative stress and cell proliferation, but the signaling cascades linked to these outcomes are unclear. To determine the role of mitogen-activated protein kinases (MAPK) in asbestos-induced cell signaling, we evaluated the effects of crocidolite asbestos, EGF and H2O2, on MAPK activation in murine lung epithelial cells (C10 line). In contrast to rapid and transient activation of extracellular signal-regulated kinase 5 (ERK5) by EGF or H2O2, asbestos caused protracted oxidant-dependent ERK5 activation that was inhibited by an Src kinase inhibitor (PP2), but not by an inhibitor of epidermal growth factor receptor (EGFR) phosphorylation (AG1478). ERK1/2 activation by asbestos was inhibited by either PP2 or AG1478. To confirm the involvement of Src in ERK1/2 and ERK5 activation, a dominant-negative Src construct was used. These experiments showed that Src was essential for ERK1/2and also ERK5 phosphorylation by asbestos. Time frame studies indicated immediate activation of Src by asbestos fibers, whereas EGFR phosphorylation occurred subsequently. Data suggest that asbestos causes activation of ERK5 through an EGFR-independent pathway, whereas ERK1/2 activation is dependent on Src through a mechanism involving phosphorylation of the EGFR. Furthermore, Src, ERK1/2 and ERK5 activation are essential for cell proliferation by asbestos. The use of a dominant-negative ERK5 construct caused selective downregulation of c-jun expression, whereas inhibition of Src by PP2 or MEK1 by PD98059 caused decreases in c-fos, fra-1 and c-jun expression in asbestos-exposed C10 cells. These observations may have broad relevance to cell proliferation by carcinogenic mineral fibers and oxidants.
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References
Abe M, Kuo W-L, MB H and Rosner M . (1999). Mol. Cell. Biol., 19, 1301–1312.
Abram C and Courtneidge S . (2000). Exp. Cell Res., 254, 1–13.
BeruBe K, Quinlan T, Fung H, Magae J, Vacek P, Taatjes D and Mossman B . (1996). Am. J. Respir. Cell. Mol. Biol., 15, 141–147.
Biscardi J, Belsches A and Parsons S . (1998). Mol. Carcinog., 21, 261–272.
Buder-Hoffmann S, Palmer C, Vacek P, Taatjes D and Mossman B . (2001). Am. J. Respir. Cell. Mol. Biol., 24, 405–413.
Campbell W, Huggins C and Wylie A . (1980). US Bureau of Mines Report of Investigations, No. 8452.
Carpenter G and Cohen S . (1990). J. Biol. Chem., 265, 7709–7712.
Esparis-Ogando A, Diaz-Rodriguez E, Montero J, Yuste L, Crespo P and Pandiella A . (2002). Mol. Cell. Biol., 22, 270–285.
Favata M, Horiuchi K, Manos E, Daulerio A, Stradley D, Feeser W, Van Dyk D, Pitts W, Earl R, Hobbs F, Copeland R, Magolda R, Scherle P and Trzaskos J . (1998). J. Biol. Chem., 273, 18623–18632.
Jimenez L, Zanella C, Fung H, Janssen Y, Vacek P, Charland C, Goldberg J and Mossman B . (1997). Am. J. Physiol. (Lung Cell. Mol. Physiol.), 273, L1029–L1035.
Kamakura S, Moriguchi T and Nishida E . (1999). J. Biol. Chem., 274, 26563–26571.
Kamp D, Israbian V, Yeldandi A, Panos R, Graceffa P and Weitzman S . (1995). Toxicol. Pathol., 23, 689–695.
Kato Y, Kravchenko V, Tapping R, Han J, Ulevitch R and Lee J . (1997). EMBO J., 16, 7054–7066.
Kato Y, Tapping R, Huang S, Watson M, Ulevitch R and Lee J . (1998). Nature, 395, 713–716.
Lee J, Ulevitch R and Han J . (1995). Biochem. Biophys. Res. Commun., 213, 715–724.
Levitzki A and Gazit A . (1995). Science, 267, 1782–1788.
Malkinson A, Dwyer-Nield L, Rice P and Dinsdale D . (1997). Toxicology, 123, 53–100.
Mohammadi M, Honegger A, Sorokin A, Ullrich A, Schlessinger J and Hurwitz D . (1993). Biochemistry, 32, 8742–8748.
Mossman B, Bignon J, Corn M, Seaton A and Gee J . (1990). Science, 247, 294–301.
Mossman B and Churg A . (1998). Am. J. Respir. Crit. Care Med., 157, 1666–1680.
Mossman B, Hubbard A, Shukla A and Timblin C . (2000). Inhal. Toxicol., 12 (Suppl. 3), 307–316.
Mossman B, Kamp D and Weitzman S . (1996). Cancer Invest., 14, 466–480.
Pache J, Janssen Y, Walsh E, Quinlan T, Zanella C, Low R, Taatjes D and Mossman B . (1998). Am. J. Pathol., 152, 333–340.
Ramos-Nino M, Haegens A, Shukla A and Mossman B . (2002a). Mol. Cell. Biochem., 234/235, 111–118.
Ramos-Nino M, Haegens A, Shukla A and Mossman B . (2002b). Mol. Cell. Biochem., 234–235, 111–118.
Ramos-Ninos M, Scapoli L, Martinelli M, Land S and Mossman B . (2003). Cancer Res., 63, 3539–3545.
Robledo R, Buder-Hoffmann S, Cummins A, Walsh E, Taatjes D and Mossman B . (2000). Am. J. Pathol., 156, 1307–1316.
Shukla A, Timblin C, Hubbard A, Bravman J and Mossman B . (2001). Cancer Res., 61, 1791–1795.
Thiery J and Chopin D . (1999). Cancer Metastasis Rev., 18, 31–42.
Wu W, Graves L, Gill G, Parsons S and Samet J . (2002). J. Biol. Chem., 277, 24252–24257.
Zanella C, Posada J, Tritton T and Mossman B . (1996). Cancer Res., 56, 5334–5338.
Zanella C, Timblin C, Cummins A, Jung M, Goldberg J, Raabe R, Tritton T and Mossman B . (1999). Am. J. Physiol. (Lung Cell. Mol. Physiol.), 277, L684–L693.
Zhou G, Bao Z and Dixon J . (1995). J. Biol. Chem., 270, 12665–12669.
Acknowledgements
This research was supported by Grants RO1 ES/HL09213 and PO1 HL67005 from NIH. We appreciate the assistance of Laurie Sabens in the preparation of this manuscript, Dr Pamela Vacek, Department of Medical Biostatistics at UVM, in the statistical analyses, and Sharon M Cawley for her technical assistance.
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Scapoli, L., Ramos-Nino, M., Martinelli, M. et al. Src-dependent ERK5 and Src/EGFR-dependent ERK1/2 activation is required for cell proliferation by asbestos. Oncogene 23, 805–813 (2004). https://doi.org/10.1038/sj.onc.1207163
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DOI: https://doi.org/10.1038/sj.onc.1207163
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