The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself.
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.
Tchen
Carmen R
CR
Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom.
Brook
Matthew
M
Saklatvala
Jeremy
J
Clark
Andrew R
AR
D020413:3' Untranslated Regions; D000241:Adenosine / Q000737:chemistry; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D011817:Rabbits; D012260:Ribonucleases / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D051816:Tristetraprolin; D014529:Uridine / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases
D020413:3' Untranslated Regions; D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D051816:Tristetraprolin; C497552:ZFP36 protein, human; C497553:Zfp36 protein, mouse; D003609:Dactinomycin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012260:Ribonucleases; D000241:Adenosine; D004318:Doxycycline; D014529:Uridine