Induction of cyclooxygenase-2 by staurosporine through the activation of nuclear factor for IL-6 (NF-IL6) and activator protein 2 (AP2) in an osteoblast-like cell line

Chiu Ya Wang, Huey Jing Lei, Chi Ying Fred Huang, Zhongjian Zhang, Anil B. Mukherjee, Chiun-Jye Yuan

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The induction of cyclooxygenase-2 (COX-2) plays a crucial role in many physiological and pathological processes. The expression of the COX-2 gene is regulated by many extracellular stimuli, including growth factors, cytokines, and tumor promoters. Staurosporine, a potential anti-tumor drug, was found recently to up-regulate the expression of the COX-2 gene in the mouse osteoblast-like cell line MC3T3-E1. The ability of staurosporine to induce the expression of the COX-2 gene was investigated using luciferase reporters controlled by various COX-2 core promoter regions. Two cis-acting sites for activator protein 2 (AP2) and nuclear factor for IL-6 (NF-IL6), respectively, were identified as responsible for the staurosporine-mediated COX-2 up-regulation. Mutational analysis further verified that both NF-IL6 and AP2 are involved in this process. Further studies showed the stimulatory effect of staurosporine on luciferase activity to be both time- and concentration-dependent. Luciferase activity could be induced at as low as 5nM staurosporine and reached a maximum at around 20nM. At 50nM, the stimulatory effect of staurosporine on luciferase activity reached a maximum at about 8hr and fell rapidly following 10hr of incubation. Interestingly, a selective protein kinase C inhibitor, 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide (GF109203X), failed to stimulate luciferase activity under the same conditions. This finding implies that staurosporine-mediated COX-2 gene expression is specific and independent of protein kinase C activity.

Original languageEnglish
Pages (from-to)177-184
Number of pages8
JournalBiochemical Pharmacology
Volume64
Issue number2
DOIs
StatePublished - 15 Jul 2002

Keywords

  • AP2
  • Cyclooxygenase-2
  • NF-IL6
  • Staurosporine

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