Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA

Mol Cell Biol. 1999 Jun;19(6):4311-23. doi: 10.1128/MCB.19.6.4311.


Mice deficient in tristetraprolin (TTP), the prototype of a family of CCCH zinc finger proteins, develop an inflammatory syndrome mediated by excess tumor necrosis factor alpha (TNF-alpha). Macrophages derived from these mice oversecrete TNF-alpha, by a mechanism that involves stabilization of TNF-alpha mRNA, and TTP can bind directly to the AU-rich element (ARE) in TNF-alpha mRNA (E. Carballo, W. S. Lai, and P. J. Blackshear, Science 281:1001-1005, 1998). We show here that TTP binding to the TNF-alpha ARE is dependent upon the integrity of both zinc fingers, since mutation of a single cysteine residue in either zinc finger to arginine severely attenuated the binding of TTP to the TNF-alpha ARE. In intact cells, TTP at low expression levels promoted a decrease in size of the TNF-alpha mRNA as well as a decrease in its amount; at higher expression levels, the shift to a smaller TNF-alpha mRNA size persisted, while the accumulation of this smaller species increased. RNase H experiments indicated that the shift to a smaller size was due to TTP-promoted deadenylation of TNF-alpha mRNA. This CCCH protein is likely to be important in the deadenylation and degradation of TNF-alpha mRNA and perhaps other ARE-containing mRNAs, both in normal physiology and in certain pathological conditions.

MeSH terms

  • Base Sequence
  • Blotting, Northern
  • Blotting, Western
  • Cell Line
  • Cytosol / metabolism
  • DNA-Binding Proteins*
  • Dactinomycin / pharmacology
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Green Fluorescent Proteins
  • Immediate-Early Proteins*
  • Kinetics
  • Luminescent Proteins / metabolism
  • Macrophages / metabolism
  • Molecular Sequence Data
  • Plasmids
  • Precipitin Tests
  • Protein Processing, Post-Translational
  • Protein Synthesis Inhibitors / pharmacology
  • Proteins / metabolism
  • Proteins / pharmacology*
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Ribonuclease H / metabolism
  • Tissue Distribution
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha / drug effects*
  • Zinc Fingers


  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Luminescent Proteins
  • Protein Synthesis Inhibitors
  • Proteins
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha
  • Green Fluorescent Proteins
  • Dactinomycin
  • Ribonuclease H