Prostaglandin endoperoxide synthase (PGHS) catalyses the rate-limiting step in the formation of prostaglandin and thromboxane eicosanoids from arachidonic acid released by phospholipase A2. Two forms of PGHS exist, PGHS-1 and PGHS-2. PGHS-2, normally absent from cells, is rapidly expressed in response to a wide variety of stimuli and has been implicated in the pathogenesis of colon cancer and several inflammatory diseases. The three principal mitogen-activated protein kinase (MAPK) pathways are the extracellular signal-regulated protein kinase (ERK), the c-Jun N-terminal kinase (JNK) cascade and the p38-MAPK cascade. The present study was undertaken to investigate the putative involvement of the MAPK cascades in PGHS-2 induction. The potential role of ERK in PGHS-2 up-regulation was assessed by using cell lines expressing, both stably and after adenoviral infection, constitutively active forms of its upstream activator MAPK/ERK kinase (MEK1). The possible involvement of JNK and p38-MAPK in positively modulating PGHS-2 transcription was investigated by using adenovirus-mediated transfer of active forms of their respective specific upstream kinases, mitogen-activated protein kinase kinase (MKK) 7 and MKK3/MKK6. ERK activation promoted the induction of PGHS-2 mRNA and protein. Similarly, activation of JNK by Ad-MKK7D and p38-MAPK by Ad-MKK3bE/Ad-MKK6bE resulted in the increased expression of PGHS-2. These results provide evidence that activation of all three of the major mammalian MAPK leads to the induction of PGHS-2 mRNA and protein. Because PGHS-2 is up-regulated by a diverse range of stimuli, both mitogenic and stress-evoking, these results provide evidence that the convergence point of these stimuli could be the activation of one or more MAPK cascade(s).
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December 2000
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Research Article|
November 24 2000
Induction of prostaglandin endoperoxide synthase 2 by mitogen-activated protein kinase cascades
Ann MCGINTY;
*Department of Medicine and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509, U.S.A.
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Marco FOSCHI;
*Department of Medicine and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509, U.S.A.
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Yu-Wen E. CHANG;
Yu-Wen E. CHANG
*Department of Medicine and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509, U.S.A.
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Jiahuai HAN;
Jiahuai HAN
†Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
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Michael J. DUNN;
Michael J. DUNN
*Department of Medicine and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509, U.S.A.
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Andrey SOROKIN
Andrey SOROKIN
4
*Department of Medicine and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509, U.S.A.
4To whom correspondence should be addressed (e-mail sorokin@mcw.edu).
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Publisher: Portland Press Ltd
Received:
April 25 2000
Revision Received:
August 11 2000
Accepted:
September 19 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 352 (2): 419–424.
Article history
Received:
April 25 2000
Revision Received:
August 11 2000
Accepted:
September 19 2000
Citation
Ann MCGINTY, Marco FOSCHI, Yu-Wen E. CHANG, Jiahuai HAN, Michael J. DUNN, Andrey SOROKIN; Induction of prostaglandin endoperoxide synthase 2 by mitogen-activated protein kinase cascades. Biochem J 1 December 2000; 352 (2): 419–424. doi: https://doi.org/10.1042/bj3520419
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