title: Serum withdrawal-induced post-transcriptional stabilization of cyclooxygenase-2 mRNA in MDA-MB-231 mammary carcinoma cells requires the activity of the p38 stress-activated protein kinase.
abstract: Overexpression of the cyclooxygenase-2 (COX-2) gene is observed in several neoplastic diseases. However, molecular mechanisms involved in the regulation of expression of COX-2 are not well understood. In this report, we describe a unique post-transcriptional regulatory mechanism of COX-2 mRNA stabilization in MDA-MB-231 cells, a highly metastatic cell line derived from a human mammary tumor. High levels of COX-2 mRNA, protein, and enzyme activity were induced by serum withdrawal, which were potently inhibited by the addition of serum or >100-kDa serum factor. Nuclear run-on analysis and actinomycin D chase experiments indicate that regulation is primarily at the level of post-transcriptional mRNA stability. Interestingly, SB203580, an inhibitor of the p38 stress-activated protein kinase (SAPK), and overexpression of the dominant-negative p38alpha construct potently inhibited the serum withdrawal-induced COX-2 mRNA levels. Indeed, the half-life of COX-2 mRNA decreased from 9 to 4.5 h after SB203580 treatment, suggesting that signal transduction by the p38 SAPK pathway is required for COX-2 mRNA stability.
authors.affiliation: Center for Vascular Biology, Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Jang
authors.forename: T
authors.initials: T
authors.lastname: Sanchez
authors.forename: H J
authors.initials: HJ
authors.lastname: Schaefers
authors.forename: O C
authors.initials: OC
authors.lastname: Trifan
authors.forename: C H
authors.initials: CH
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Creminon
authors.forename: C K
authors.initials: CK
authors.lastname: Huang
authors.forename: T
authors.initials: T
authors.lastname: Hla
mesh_terms: D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000378:metabolism; D051546:Cyclooxygenase 2; D003609:Dactinomycin / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D005799:Genes, Dominant; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D008565:Membrane Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D003609:Dactinomycin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine; D015232:Dinoprostone; C093642:SB 203580