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J. Biol. Chem., Vol. 277, Issue 12, 9728-9735, March 22, 2002
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From the Departments of Human papillomavirus (HPV) is an important
etiological agent in the genesis of cervical cancer. HPV-positive
cervical tumors and human papillomavirus-positive cell lines display
increased epidermal growth factor receptor (EGFR) expression, which is
associated with increased cell proliferation. ECE16-1 cells are an
HPV-immortalized human ectocervical epithelial cell line that is a
model of HPV-associated cervical neoplasia and displays elevated EGFR
levels. In the present study, we evaluated the effects of
receptor-selective retinoid ligands on EGFR-associated signal
transduction. We show that retinoic acid receptor (RAR)-selective
ligands reduce EGFR level and the magnitude and duration of EGFR
activation in EGF-stimulated cells. These effects are reversed by
cotreatment with an RAR antagonist. To identify the mechanism, we
examined the effects of retinoid treatments on
EGF-dependent signaling. Stimulation with EGF causes a
biphasic activation of the ERK1/2 MAPK. The first peak of activation is
present at 20 min, and the second is present at 36 h. This activation subsequently leads to an increase in the cyclin D1 level and
increased cell proliferation. Simultaneous treatment with EGF and a
RAR-selective retinoid inhibits both phases of ERK1/2 activation,
completely eliminates the cyclin D1 induction, and suppresses
EGF-dependent cell proliferation. This effect is specific
as retinoid treatment does not alter the level or activity of other
EGFR-regulated kinases, including AKT and the MAPKs p38 and JNK.
Retinoid X receptor-selective ligands, in contrast, did not
regulate these responses. These results suggest that RAR
ligand-associated down-regulation of EGFR activity reduces cell
proliferation by reducing the magnitude and duration of
EGF-dependent ERK1/2 activation.
Retinoids Suppress Epidermal Growth Factor-associated Cell
Proliferation by Inhibiting Epidermal Growth Factor
Receptor-dependent ERK1/2 Activation*
,
**
Environmental Health
Sciences, § Physiology and Biophysics, and
Reproductive Biology, Case Western Reserve University School
of Medicine, Cleveland, Ohio 44106 and ¶ Retinoid Research,
Allergan Pharmaceuticals, Inc., Irvine, California 92612
*
This work was supported by a grant from Ohio Cancer
Research Associates, National Institutes of Health Grant RO-1 ES09126 (to E. A. R.), and a grant from Allergan, Inc. (to R. L. E.).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.
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