AU-rich Element-Mediated Translational Control: Complexity and Multiple Activities of Trans-Activating Factors

Biochem Soc Trans. 2002 Nov;30(Pt 6):952-8. doi: 10.1042/bst0300952.


Tumour necrosis factor (TNF)-alpha mRNA contains an AU-rich element (ARE) in its 3' untranslated region (3'UTR), which determines its half-life and translational efficiency. In unstimulated macrophages, TNF-alpha mRNA is repressed translationally, and becomes efficiently translated upon cell activation. Gel retardation experiments and screening of a macrophage cDNA expression library with the TNF-alpha ARE allowed the identification of TIA-1-related protein (TIAR), T-cell intracellular antigen-1 (TIA-1) and tristetraprolin (TTP) as TNF-alpha ARE-binding proteins. Whereas TIAR and TIA-1 bind the TNF-alpha ARE independently of the activation state of macrophages, the TTP-ARE complex is detectable upon stimulation with lipopolysaccharide (LPS). Moreover, treatment of LPS-induced macrophage extracts with phosphatase significantly abrogates TTP binding to the TNF-alpha ARE, indicating that TTP phosphorylation is required for ARE binding. Carballo, Lai and Blackshear [(1998) Science 281, 1001-1005] showed that TTP was a TNF-alpha mRNA destabilizer. In contrast, TIA-1, and most probably TIAR, acts as a TNF-alpha mRNA translational silencer. A two-hybrid screening with TIAR and TIA-1 revealed the capacity of these proteins to interact with other RNA-binding proteins. Interestingly, TIAR and TIA-1 are not engaged in the same interaction, indicating for the first time that TIAR and TIA-1 can be functionally distinct. These findings also suggest that ARE-binding proteins interact with RNA as multimeric complexes, which might define their function and their sequence specificity.

Publication types

  • Review

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • DNA-Binding Proteins*
  • Gene Expression Regulation*
  • Immediate-Early Proteins / metabolism
  • Lipopolysaccharides / metabolism
  • Mice
  • Models, Biological
  • Protein Binding
  • Protein Biosynthesis
  • RNA Stability
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism
  • Transcriptional Activation*
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha / metabolism


  • 3' Untranslated Regions
  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Lipopolysaccharides
  • RNA, Messenger
  • RNA-Binding Proteins
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha
  • Zfp36 protein, mouse