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

Overview

MeSH Major

  • Antineoplastic Combined Chemotherapy Protocols
  • Breast Neoplasms
  • Clinical Trials as Topic
  • Neoadjuvant Therapy
  • Neoplasm, Residual
  • Practice Guidelines as Topic

abstract

  • We investigated whether microtubule-interfering agents (MIAs: taxol, colchicine, nocodazole, vinblastine, vincristine, 17-beta-estradiol, 2-methoxyestradiol) altered cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. MIAs enhanced prostaglandin E(2) 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.

publication date

  • May 19, 2000

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1074/jbc.275.20.14838

PubMed ID

  • 10809726

Additional Document Info

start page

  • 14838

end page

  • 45

volume

  • 275

number

  • 20