| 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
|
|
WOS Category
|
RESPIRATORY SYSTEM
PHYSIOLOGY
|
| Resource |
| DNA material |
pBS rcjun-1 Rat c-Jun protooncogene (RDB01130) |
