c-Jun N-terminal Kinase-mediated Stabilization of Microsomal Prostaglandin E2 Synthase-1 mRNA Regulates Delayed Microsomal Prostaglandin E2 Synthase-1 Expression and Prostaglandin E2 Biosynthesis by Cardiomyocytes*

  1. Barry B. Rubin,3
  1. Divisions of Vascular Surgery and §Cardiac Surgery, Toronto General Hospital Research Institute of the University Health Network, University of Toronto, Toronto, Ontario M5G-2C4, Canada, the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden, the Renal Division and Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario M5S-1A8, Canada, and **Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340
  1. 2 To whom correspondence may be addressed: Dept. of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden. Tel.: 46-8-52487652; Fax: 46-8-736-0439; E-mail: per-johan.jakobsson{at}mbb.ki.se. 3 Wylie Scholar in Academic Vascular Surgery, Pacific Vascular Research Foundation, San Francisco. To whom correspondence may be addressed: Division of Vascular Surgery, 200 Elizabeth St., EC5-302a, Toronto General Hospital, Toronto, Ontario M5G-2C4, Canada. Tel.: 416-340-3645; Fax: 416-340-5029; E-mail: barry.rubin{at}uhn.on.ca.


Microsomal prostaglandin (PG) E2 synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE2, a key proinflammatory mediator. The purpose of this study was to elucidate the regulation of mPGES-1 mRNA expression in cardiomyocytes, define the role of JNK enzymes in this process, and characterize the role of mPGES-1 in cardiomyocyte PGE2 biosynthesis. In neonatal cardiomyocytes, interleukin-1β and lipopolysaccharide (LPS) both stimulated mPGES-1 mRNA expression and increased mPGES-1 mRNA stability and protein synthesis but failed to increase mPGES-1 mRNA transcription. Treatment with the JNK1/2 inhibitor, SP600125, abrogated the increases in mPGES-1 mRNA stability, mPGES-1 protein synthesis, and PGE2 release induced by interleukin-1β or LPS. mPGES-1 protein synthesis was observed in LPS-stimulated neonatal cardiomyocytes from jnk1–/– or jnk2–/– mice. In contrast, infection of jnk1–/– cardiomyocytes with an adenovirus encoding phosphorylation-resistant JNK2 (ad-JNK2-DN), or of jnk2–/– cardiomyocytes with ad-JNK1-DN, significantly decreased LPS-stimulated mPGES-1 protein synthesis. Similarly, co-infection with ad-JNK1-DN and ad-JNK2-DN attenuated LPS-stimulated mPGES-1 protein synthesis in cardiomyocytes from wild type mice. Targeted deletion of the gene encoding mPGES-1 led to a 3.2-fold decrease in LPS-stimulated PGE2 release by cardiomyocytes in comparison with wild type cells but had no effect on COX-1, COX-2, mPGES-2, or cytosolic PGES mRNA levels. These studies provide direct evidence that mPGES-1 mRNA levels in cardiomyocytes are augmented by stabilization of mPGES-1 mRNA, that JNK1 or JNK2 can participate in the regulation of mPGES-1 protein synthesis in these cells, and that mPGES-1 catalyzes the majority of LPS-induced PGE2 biosynthesis by cardiomyocytes.

  • Received March 24, 2006.
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This Article

  1. The Journal of Biological Chemistry 281, 16443-16452.
  1. All Versions of this Article:
    1. M602815200v1
    2. 281/24/16443 (most recent)

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