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

Carmen R Tchen, Matthew Brook, Jeremy Saklatvala, Andrew R Clark

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Pages (from-to)32393-400
Number of pages8
JournalJournal of Biological Chemistry
Issue number31
Publication statusPublished - 30 Jul 2004


  • 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


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