The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself.

Journal article

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.

Authors: Tchen, C; Brook, M; Saklatvala, J; Clark, A

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 279
• Issue: 31
• Pages: 32393-32400
• Publication date: 2004-07-01
• DOI: 10.1074/jbc.m402059200
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Humans; Mice; Ribonucleases; RNA Processing, Post-Transcriptional; Blotting, Western; Dose-Response Relationship, Drug; Immediate-Early Proteins; Protein Synthesis Inhibitors; Nucleic Acid Synthesis Inhibitors; p38 Mitogen-Activated Protein Kinases; Blotting, Northern; Sequence Homology, Nucleic Acid; Adenosine; Cell Line; Tristetraprolin; Lipopolysaccharides; RNA, Messenger; 3' Untranslated Regions; Hela Cells; Macrophages; Rabbits; DNA-Binding Proteins; Anti-Bacterial Agents; Transcription, Genetic; Transfection; MAP Kinase Signaling System; Dactinomycin; Animals; Cytoplasm; Base Sequence; Uridine; Time Factors; Mitogen-Activated Protein Kinases; Doxycycline; Molecular Sequence Data