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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

J Biol Chem

Publication Date

30/07/2004

Volume

279

Pages

32393 - 32400

Keywords

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