Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability

Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protei n kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-alpha) mRNA in myeloid cells stimulated with bacterial lipopoly saccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expresse d 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 bindin g of TTP to the TNF-alpha 3' untranslated region. The p38 pathway is requir ed for the induction of TNF-alpha RNA-binding activity and for the expressi on of TTP protein and mRNA. Following stimulation with LPS, TTP is expresse d in multiple, differentially phosphorylated forms. We present evidence tha t phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 ( MAPK-activated protein kinase 2). Our findings demonstrate a direct link be tween a specific signal transduction pathway and a specific RNA-binding pro tein, both of which are known to regulate TNF-alpha gene expression at a po sttranscriptionaI level.