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Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-alpha) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-alpha mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-alpha 3' untranslated region. The p38 pathway is required for the induction of TNF-alpha RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-alpha gene expression at a posttranscriptional level.

Original publication

DOI

10.1128/mcb.21.9.6461-6469.2001

Type

Journal article

Journal

Molecular and Cellular Biology

Publication Date

10/2001

Volume

21

Pages

6461 - 6469

Addresses

Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, Hammersmith, London W6 8LH, United Kingdom.

Keywords

Cell Line, Animals, Humans, Mice, Macromolecular Substances, Protein-Serine-Threonine Kinases, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Lipopolysaccharides, Tumor Necrosis Factor-alpha, Intracellular Signaling Peptides and Proteins, RNA-Binding Proteins, DNA-Binding Proteins, Immediate-Early Proteins, RNA, Messenger, 3' Untranslated Regions, Cell Extracts, MAP Kinase Signaling System, Transcription, Genetic, Protein Processing, Post-Translational, RNA Stability, Phosphorylation, Kinetics, Tristetraprolin