RRC ID 12185
Author Zanella CL, Timblin CR, Cummins A, Jung M, Goldberg J, Raabe R, Tritton TR, Mossman BT.
Title Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis.
Journal Am J Physiol
Abstract We examined the mechanisms of interaction of crocidolite asbestos fibers with the epidermal growth factor (EGF) receptor (EGFR) and the role of the EGFR-extracellular signal-regulated kinase (ERK) signaling pathway in early-response protooncogene (c-fos/c-jun) expression and apoptosis induced by asbestos in rat pleural mesothelial (RPM) cells. Asbestos fibers, but not the nonfibrous analog riebeckite, abolished binding of EGF to the EGFR. This was not due to a direct interaction of fibers with ligand, inasmuch as binding studies using fibers and EGF in the absence of membranes showed that EGF did not adsorb to the surface of asbestos fibers. Exposure of RPM cells to asbestos caused a greater than twofold increase in steady-state message and protein levels of EGFR (P < 0.05). The tyrphostin AG-1478, which inhibits the tyrosine kinase activity of the EGFR, but not the tyrphostin A-10, which does not affect EGFR activity, significantly ameliorated asbestos-induced increases in mRNA levels of c-fos but not of c-jun. Pretreatment of RPM cells with AG-1478 significantly reduced apoptosis in cells exposed to asbestos. Our findings suggest that asbestos-induced binding to EGFR initiates signaling pathways responsible for increased expression of the protooncogene c-fos and the development of apoptosis. The ability to block asbestos-induced elevations in c-fos mRNA levels and apoptosis by small-molecule inhibitors of EGFR phosphorylation may have therapeutic implications in asbestos-related diseases.
Volume 277(4)
Pages L684-93
Published 1999-10-1
DOI 10.1152/ajplung.1999.277.4.L684
PMID 10516208
MeSH Animals Apoptosis / physiology* Asbestos, Crocidolite / pharmacology* Cells, Cultured Epidermal Growth Factor / antagonists & inhibitors Epidermal Growth Factor / metabolism Epidermal Growth Factor / pharmacology Epithelial Cells / metabolism ErbB Receptors / genetics ErbB Receptors / metabolism* ErbB Receptors / physiology Gene Expression Regulation / physiology Homeostasis / drug effects Phosphorylation Pleura / cytology Pleura / metabolism Proto-Oncogene Proteins c-fos / genetics Proto-Oncogene Proteins c-fos / metabolism* RNA, Messenger / metabolism Rats Rats, Inbred F344 Signal Transduction / physiology
IF 3.485
Times Cited 68
DNA material pBS rcjun-1 Rat c-Jun protooncogene (RDB01130)