title: Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2. Evidence for involvement of ERK1/2 AND p38 mitogen-activated protein kinase pathways.
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.
authors.affiliation: Department of Medicine, New York Presbyterian Hospital-Cornell and Strang Cancer Prevention Center, New York, New York 10021, USA. ksubba@mail.med.cornell.edu
authors.forename: K
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: J C
authors.initials: JC
authors.lastname: Hart
authors.forename: L
authors.initials: L
authors.lastname: Norton
authors.forename: A J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000077584:2-Methoxyestradiol; D001940:Breast / Q000166:cytology; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D051546:Cyclooxygenase 2; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D007700:Kinetics; D008565:Membrane Proteins; D008870:Microtubules / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D014158:Transcription, Genetic; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D004958:Estradiol; D014750:Vincristine; D014747:Vinblastine; D000077584:2-Methoxyestradiol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D015739:Nocodazole; D003078:Colchicine