Tristetraprolin Regulates CXCL1 (KC) mRNA Stability

摘要: mRNAs encoding proinflammatory chemokines are regulated posttranscriptionally via adenine-uridine-rich sequences (AREs) located in the 3′ untranslated region of message, which recognized by sequence-specific RNA-binding proteins. One ARE binding protein, tristetraprolin (TTP), has been implicated regulating stability several ARE-containing mRNAs, including those TNF-α and GM-CSF. In present report we examined role TTP decay mouse chemokine KC (CXCL1) mRNA. Using tetR-regulated control transcription TTP-deficient HEK293 cells, mRNA half-life was markedly decreased presence TTP. Deletion site-specific mutagenesis were used to identify multiple AUUUA sequence determinants responsible for sensitivity. Although a number studies suggest that destabilizing activity is subject modulation response ligands Toll/IL-1 family receptors, mediated 293 cells not sensitive stimulation with IL-1α. primary macrophages from wild-type mice, instability found be highly dependent on Furthermore, LPS-mediated stabilization blocked inhibition p38 MAPK but mice. These findings demonstrate predominant regulator mononuclear phagocytes acting 3′-untranslated region-localized AREs. Nevertheless, remains unstable do express TTP, suggesting additional stimulus sensitivity may operate cell populations where expressed.