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. |
Publication Type | Journal Article |
Year of Publication | 2000 |
Authors | Jang BC, Sanchez T, Schaefers HJ, Trifan OC, Liu CH, Creminon C, Huang CK, Hla T |
Journal | J Biol Chem |
Volume | 275 |
Issue | 50 |
Pagination | 39507-15 |
Date Published | 2000 Dec 15 |
ISSN | 0021-9258 |
Keywords | Apoptosis, Blotting, Northern, Blotting, Western, Breast Neoplasms, Bromodeoxyuridine, Cell Cycle, Cell Nucleus, Culture Media, Serum-Free, Cyclooxygenase 2, Dactinomycin, Dinoprostone, Dose-Response Relationship, Drug, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Genes, Dominant, Humans, Imidazoles, Isoenzymes, Membrane Proteins, Microscopy, Fluorescence, Mitogen-Activated Protein Kinases, Nucleic Acid Synthesis Inhibitors, p38 Mitogen-Activated Protein Kinases, Prostaglandin-Endoperoxide Synthases, Pyridines, RNA Processing, Post-Transcriptional, RNA, Messenger, Signal Transduction, Time Factors, Transfection, Tumor Cells, Cultured |
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. |
DOI | 10.1074/jbc.M003224200 |
Alternate Journal | J Biol Chem |
PubMed ID | 10993880 |
Grant List | HL49094 / HL / NHLBI NIH HHS / United States HL54710 / HL / NHLBI NIH HHS / United States |
Related Faculty:
Teresa Sanchez, Ph.D.