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Tristetraprolin (TTP) is an mRNA-destabilizing protein that negatively regulates the expression of proinflammatory mediators such as tumor necrosis factor alpha, granulocyte/macrophage colony-stimulating factor, and cyclooxygenase 2. Here we investigate the regulation of TTP expression in the mouse macrophage cell line RAW264.7. We show that TTP mRNA is expressed in a biphasic manner following stimulation of cells with lipopolysaccharide and that the second phase of expression, like the first, is dependent on mitogen-activated protein kinase (MAPK) p38. MAPK p38 acts through a downstream kinase to stabilize TTP mRNA, and this stabilization is mediated by an adenosine/uridine-rich region at the 3'-end of the TTP 3'-untranslated region. Hence TTP is post-transcriptionally regulated in a similar manner to several proinflammatory genes. We also demonstrate that TTP is able to bind to its own 3'-untranslated region and negatively regulate its own expression, forming a feedback loop to limit expression levels.

Original publication

DOI

10.1074/jbc.m402059200

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

07/2004

Volume

279

Pages

32393 - 32400

Addresses

Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom.

Keywords

Cell Line, Hela Cells, Cytoplasm, Macrophages, Animals, Rabbits, Humans, Mice, Dactinomycin, Doxycycline, Ribonucleases, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Lipopolysaccharides, DNA-Binding Proteins, Immediate-Early Proteins, RNA, Messenger, 3' Untranslated Regions, Adenosine, Uridine, Nucleic Acid Synthesis Inhibitors, Protein Synthesis Inhibitors, Anti-Bacterial Agents, Blotting, Western, Blotting, Northern, Transfection, MAP Kinase Signaling System, Transcription, Genetic, RNA Processing, Post-Transcriptional, Base Sequence, Sequence Homology, Nucleic Acid, Dose-Response Relationship, Drug, Time Factors, Molecular Sequence Data, Tristetraprolin