Cardiac hypertrophy, an important adaptational response, is associated with up-regulation of the immediate early gene, c-jun, which encodes the c-Jun transcription factor. c-Jun may feed back to up-regulate its own transcription and, since the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) phosphorylate c-Jun(Ser-63/73) to increase its transactivating activity, JNKs are thought to be the principal factors involved in c-jun up-regulation. Hypertrophy in primary cultures of cardiac myocytes is induced by endothelin-1, phenylephrine or PMA, probably through activation of one or more of the MAPK family. These three agonists increased c-jun mRNA with the rank order of potency of PMAendothelin-1> phenylephrine. Up-regulation of c-jun mRNA by endothelin-1 was attenuated by inhibitors of protein kinase C (GF109203X) and the extracellular signal-regulated kinase (ERK) cascade (PD98059 or U0126), but not by inhibitors of the JNK (SP600125) or p38-MAPK (SB203580) cascades. Hyperosmotic shock (0.5M sorbitol) powerfully activates JNKs, but did not increase c-jun mRNA. These data suggest that ERKs, rather than JNKs, are required for c-jun up-regulation. However, endothelin-1 and phenylephrine induced greater up-regulation of c-Jun protein than PMA and phosphorylation of c-Jun(Ser-63/73) correlated with the level of c-Jun protein. Up-regulation of c-Jun protein by endothelin-1 was attenuated by inhibitors of protein kinase C and the ERK cascade, probably correlating with a primary input of ERKs into transcription. In addition, SP600125 inhibited the phosphorylation of c-Jun(Ser-63/73), attenuated the increase in c-Jun protein induced by endothelin-1 and increased the rate of c-Jun degradation. Thus whereas ERKs are the principal MAPKs required for c-jun transcription, JNKs are necessary to stabilize c-Jun for efficient up-regulation of the protein.
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November 2002
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Research Article|
November 15 2002
Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun N-terminal kinases are required for efficient up-regulation of c-Jun protein
Angela CLERK;
Angela CLERK
1
∗Cardiac Medicine Section, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.,
1To whom correspondence should be addressed, at Division of Biomedical Sciences, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, U.K. (e-mail a.clerk@ic.ac.uk).
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Timothy J. KEMP;
Timothy J. KEMP
∗Cardiac Medicine Section, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.,
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Joanne G. HARRISON;
Joanne G. HARRISON
∗Cardiac Medicine Section, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.,
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Anthony J. MULLEN;
Anthony J. MULLEN
†Cardiothoracic Surgery Section, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
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Paul J.R. BARTON;
Paul J.R. BARTON
†Cardiothoracic Surgery Section, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
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Peter H. SUGDEN
Peter H. SUGDEN
∗Cardiac Medicine Section, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.,
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Publisher: Portland Press Ltd
Received:
July 10 2002
Revision Received:
August 05 2002
Accepted:
August 08 2002
Accepted Manuscript online:
August 08 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 368 (1): 101–110.
Article history
Received:
July 10 2002
Revision Received:
August 05 2002
Accepted:
August 08 2002
Accepted Manuscript online:
August 08 2002
Citation
Angela CLERK, Timothy J. KEMP, Joanne G. HARRISON, Anthony J. MULLEN, Paul J.R. BARTON, Peter H. SUGDEN; Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun N-terminal kinases are required for efficient up-regulation of c-Jun protein. Biochem J 15 November 2002; 368 (1): 101–110. doi: https://doi.org/10.1042/bj20021083
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