The roles of TTP and BRF proteins in regulated mRNA decay

TIS11 plays a central role in posttranscriptional regulation of gene expression. Tristetraprolin (TTP) and the other TIS11 family members butyrate response factors 1 and 2 (BRF‐1 and BRF‐2) bind to adenylate‐ and uridylate‐rich elements (ARE) in the 3^′ untranslated region of mRNA transcripts. Through their direct and indirect association with components of the deadenylase complex such as Ccr4, Caf1, and PARN, TIS11 family members promote rapid mRNA deadenylation. TTP and BRF proteins target the deadenylated mRNA transcript for storage or decay in P‐bodies. Once in P‐bodies, TTP interacts with the mRNA decapping complex and activates mRNA decapping. After decapping, the mRNA body undergoes 5′→3′ exonucleolytic decay. P‐bodies are closely associated with cellular stress granules, and TTP possibly mediates the transport of translationally repressed ARE‐containing mRNAs from stress granules to be decayed in P‐bodies. With regard to 3′→5′ mediated decay, TTP associates with components of the exosome and targets the mRNA for 3′→5′ exosome‐mediated degradation.

Loss of tristetraprolin (TTP) expression promotes chronic inflammation and progression of tumorigenesis. In normal cells, expression of TTP allows the controlled expression of a variety of cancer‐ and inflammation‐associated genes by selectively targeting these adenylate‐ and uridylate‐rich element (ARE)‐containing mRNA transcripts for rapid decay. Loss of TTP expression promotes chronic inflammation and is observed during tumorigenesis, thereby allowing stabilization of ARE‐containing transcripts. This selective ARE‐mRNA stabilization contributes to overexpression of factors such as COX‐2, tumor necrosis factor‐α, cyclin D1, and vascular endothelial growth factor that promote chronic inflammation, resistance to apoptosis, enhanced cell growth and proliferation, and increased angiogenesis and metastasis.