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J Biol Chem, Vol. 274, Issue 41, 29138-29148, October 8, 1999
From the Treatment of normal human epidermal keratinocytes
(NHEK) with interferon-
Regulation of Cyclooxygenase-2 by Interferon
and Transforming
Growth Factor 
in Normal Human Epidermal Keratinocytes and Squamous
Carcinoma Cells
ROLE OF MITOGEN-ACTIVATED PROTEIN KINASES
§,§,
,,, and
Cell Biology Section, New
York Presbyterian Hospital Strang Cancer Prevention Center and Weill
Medical College of Cornell University, Division of Digestive Diseases,
New York, New York 10021, the § Department of Pharmacology,
National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai,
Osaka, Suita, 565-8565, Japan, and the
Department of Dermatology, Okayama
University Medical School, Shikata-chô 2-5-1, Okayama 700, Japan
(IFN-) causes a 9-fold increase in the
level of cyclooxygenase-2 (COX-2) mRNA expression. Nuclear run-off
assays indicate that this induction is at least partly due to increased transcription. Activation of the epidermal growth factor receptor (EGFR) signaling pathway due to the enhanced transforming growth factor
(TGF) expression plays an important role in the induction of
COX-2 by IFN-. This is supported by the ability of TGF to rapidly
induce COX-2 and the inhibition of the IFN--mediated COX-2 mRNA
induction by an EGFR antibody and EGFR-selective kinase inhibitors.
Deletion and mutation analysis indicates the importance of the proximal
cAMP-response element/ATF site in the transcriptional control of this
gene by TGF. The increase in COX-2 mRNA by TGF requires
activation of both the extracellular signal-regulated kinase (ERK) and
p38 mitogen-activated protein kinase (MAPK) pathways. Inhibition of p38
MAPK decreases the stability of COX-2 mRNA, while inhibition of
MAPK/ERK kinase (MEK) does not. These results suggest that the p38 MAPK
signaling pathway controls COX-2 at the level of mRNA stability,
while the ERK signaling pathway regulates COX-2 at the level of
transcription. In contrast to NHEK, IFN- and TGF are not very
effective in inducing TGF or COX-2 expression in several squamous
carcinoma cell lines, indicating alterations in both IFN- and TGF
response pathways.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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