Abstract
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.
MeSH terms
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3' Untranslated Regions
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Adenosine / chemistry
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Animals
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Anti-Bacterial Agents / pharmacology
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Base Sequence
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Blotting, Northern
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Blotting, Western
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Cell Line
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Cytoplasm / metabolism
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DNA-Binding Proteins*
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Dactinomycin / pharmacology
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Dose-Response Relationship, Drug
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Doxycycline / pharmacology
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HeLa Cells
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Humans
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Immediate-Early Proteins / chemistry*
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Lipopolysaccharides / metabolism
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MAP Kinase Signaling System
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Macrophages / metabolism
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Mice
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Mitogen-Activated Protein Kinases / metabolism*
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Molecular Sequence Data
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Protein Synthesis Inhibitors / pharmacology
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RNA Processing, Post-Transcriptional
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RNA, Messenger / metabolism*
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Rabbits
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Ribonucleases / metabolism
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Sequence Homology, Nucleic Acid
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Time Factors
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Transcription, Genetic
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Transfection
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Tristetraprolin
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Uridine / chemistry
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p38 Mitogen-Activated Protein Kinases
Substances
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3' Untranslated Regions
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Anti-Bacterial Agents
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DNA-Binding Proteins
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Immediate-Early Proteins
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Lipopolysaccharides
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Nucleic Acid Synthesis Inhibitors
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Protein Synthesis Inhibitors
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RNA, Messenger
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Tristetraprolin
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ZFP36 protein, human
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Zfp36 protein, mouse
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Dactinomycin
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Ribonucleases
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Adenosine
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Doxycycline
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Uridine