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Activation of the EGF receptor signaling pathway in human airway epithelial cells exposed to metals
1 Center for Environmental Medicine and Lung Biology and 2 Department of Pharmacology, University of North Carolina, Chapel Hill 27599; and 3 Human Studies Division, National Health Effects and Environmental Research Laboratory, United States Environmental Protection Agency, Research Triangle Par...
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Published in: | American journal of physiology. Lung cellular and molecular physiology 1999-11, Vol.277 (5), p.924-L931 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 1 Center for Environmental
Medicine and Lung Biology and
2 Department of Pharmacology,
University of North Carolina, Chapel Hill 27599; and
3 Human Studies Division,
National Health Effects and Environmental Research Laboratory,
United States Environmental Protection Agency, Research Triangle
Park, North Carolina 27711
We have previously shown that exposure to
combustion-derived metals rapidly (within 20 min) activated
mitogen-activated protein kinases (MAPK), including extracellular
signal-regulated kinase (ERK), in the human bronchial epithelial cell
line BEAS. To study the mechanisms responsible for metal-induced
activation of ERK, we examined the effect of noncytotoxic exposures to
As, Cu, V, or Zn on the kinases upstream of ERK in the epidermal growth
factor (EGF) receptor signaling pathway. Western blotting using
phospho-specific ERK1/2 antibody demonstrated the selective MEK1/2
inhibitor PD-98059 blocked metal-induced phosphorylation of ERK1/2.
Meanwhile, Western blotting using a phospho-specific MEK1/2 antibody
showed that these metals induce a rapid phosphorylation of MEK1/2.
Kinase activity assays confirmed the activation of MEK1/2 by metal
treatment. Immunoprecipitation studies demonstrated that As, Cu, V, or
Zn induces EGF receptor phosphorylation. Furthermore, the EGF
receptor-specific tyrosine kinase inhibitor (PD-153035) significantly
blocked the phosphorylation of MEK1/2 initiated by metals.
Interestingly, we observed low levels of Raf-1 activity that were not
increased by metal exposure in these cells through kinase activity
assay. Finally, transfection assays showed that MEK1/2 inhibition could inhibit trans -activation of Elk1, a
transcription factor in the ERK pathway, in BEAS cells exposed to
metals. Together, these data demonstrate that As, Cu, V, and Zn can
activate the EGF receptor signaling pathway in BEAS cells and suggest
that this mechanism may be involved in pulmonary responses to metal inhalation.
signal transduction; air pollution; epidermal growth factor
receptor; mitogen-activated protein kinase kinase |
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ISSN: | 1040-0605 1522-1504 |
DOI: | 10.1152/ajplung.1999.277.5.l924 |