Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2. Evidence for involvement of ERK1/2 and p38 mitogen- activated protein kinase pathways

Kotha Subbaramaiah, Janice C. Hart, Larry Norton, Andrew J. Dannenberg

Research output: Contribution to journalArticle

292 Scopus citations

Abstract

We investigated whether microtubule-interfering agents (MIAs: taxol, colchicine, nocodazole, vinblastine, vincristine, 17-β-estradiol, 2- methoxyestradiol) altered cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. MIAs enhanced prostaglandin E2 synthesis and increased levels of COX-2 protein and mRNA. Nuclear run-off assays revealed increased rates of COX-2 transcription after treatment with MIAs. Calphostin C, an inhibitor of protein kinase C, blocked the induction of COX-2 by MIAs. The stimulation of COX-2 promoter activity by MIAs was inhibited by overexpressing dominant negative forms of Rho and Raf-1. MIAs stimulated ERK, JNK, and p38 mitogen-activated protein kinases (MAPK); pharmacological inhibitors of MAPK kinase and p38 MAPK blocked the induction of COX-2 by MIAs. Overexpressing dominant negative forms of ERK1 or p38 MAPK inhibited MIA-mediated activation of the COX-2 promoter, MIAs stimulated the binding of the activator protein-1 transcription factor complex to the cyclic AMP response element in the COX-2 promoter. A dominant negative form of c-Jun inhibited the activation of the COX-2 promoter by MIAs. Additionally, cytochalasin D, an agent that inhibits actin polymerization, stimulated COX-2 transcription by the same signaling pathway as MIAs. Thus, microtubule-or actin-interfering agents stimulated MAPK signaling and activator protein-1 activity. This led, in turn, to induction of COX-2 gene expression via the cyclic AMP response element site in the COX-2 promoter.

Original languageEnglish (US)
Pages (from-to)14838-14845
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number20
DOIs
StatePublished - May 19 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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