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J. Biol. Chem., Vol. 277, Issue 4, 2945-2950, January 25, 2002
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From TMBB, HELD, National Institute for Occupational Safety
and Health, Centers for Disease Control, Morgantown,
West Virginia 26505
Environmental or occupational exposure to arsenic
is associated with a greatly increased risk of skin, urinary bladder,
and respiratory tract cancers in arseniasis-endemic areas throughout the world. Arsenic shares many properties of tumor promoters by affecting specific cell signal transduction pathways responsible for
cell proliferation. The activation of the epidermal growth factor
receptor (EGFR)-extracellular signal-regulated protein kinase (ERK)
pathway is important in mediating gene expression related to regulation
of cellular growth. In the current studies, we demonstrate that arsenic
activates EGFR and ERK in a human uroepithelial cell line. The EGFR
phosphorylation by arsenic is ligand-independent and does not involve
the major autophosphorylation site Tyr1173. c-Src
activity is also induced by arsenic and is a prerequisite for the EGFR
and ERK activation. Consistent with these in vitro observations, exposure of mice to arsenic in drinking water, which has
been found previously to be associated with AP-1 activation and
epithelial proliferation, induces EGFR and ERK activation in the
urinary bladder. This response is also accompanied with an increase in
c-Src levels interacting with EGFR. These findings represent a
potential pathway for mediating arsenic-induced phenotypic changes in the uroepithelium.
c-Src-dependent Activation of the Epidermal Growth
Factor Receptor and Mitogen-activated Protein Kinase Pathway by
Arsenic
ROLE IN CARCINOGENESIS*
,
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 304-285-6156;
Fax: 304-285-6038; E-mail: PSimeonova@cdc.gov.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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