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Review
. 2011 Jan-Feb;2(1):42-57.
doi: 10.1002/wrna.28.

The roles of TTP and BRF proteins in regulated mRNA decay

Sandhya Sanduja  1 , Fernando F Blanco, Dan A Dixon
Affiliations
Review

The roles of TTP and BRF proteins in regulated mRNA decay

Sandhya Sanduja et al. Wiley Interdiscip Rev RNA. 2011 Jan-Feb.

Abstract

Adenylate- and uridylate-rich element (ARE) motifs are cis-acting elements present in the 3′ untranslated region of mRNA transcripts that encode many inflammation- and cancer-associated genes. The TIS11 family of RNA-binding proteins, composed of tristetraprolin (TTP) and butyrate response factors 1 and 2 (BRF-1 and -2), plays a critical role in regulating the expression of ARE-containing mRNAs. Through their ability to bind and target ARE-containing mRNAs for rapid degradation, this class of RNA-binding proteins serves a fundamental role in limiting the expression of a number of critical genes, thereby exerting anti-inflammatory and anti-cancer effects. Regulation of TIS11 family members occurs on a number of levels through cellular signaling events to control their transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TIS11 members' ability to promote ARE-mediated mRNA decay along with decay-independent functions. This review summarizes our current understanding of posttranscriptional regulation of ARE-containing gene expression by TIS11 family members and discusses their role in maintaining normal physiological processes and the pathological consequences in their absence.

Keywords: AU-rich element; Butyrate Response Factor; Tristetraprolin; mRNA decay; post-transcriptional regulation.

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Figures

Figure 1
Figure 1. TIS11 plays a central role in post-transcriptional regulation of gene expression
TTP and the other TIS11 family members BRF-1 and BRF-2 bind to AU-rich elements in the 3′UTR 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.
Figure 2
Figure 2. Loss of TTP expression promotes chronic inflammation and progression of tumorigenesis
In normal cells, expression of TTP allows for the controlled expression of a variety of cancer- and inflammation-associated genes by selectively targeting these ARE-containing mRNA transcripts for rapid decay. Loss of TTP expression promotes chronic inflammation and is observed during tumorigenesis, thereby allowing for stabilization of ARE-containing transcripts. This selective ARE mRNA stabilization contributes to overexpression of factors such as COX-2, TNF-α, cyclin D1, and VEGF that promote chronic inflammation, resistance to apoptosis, enhanced cell growth and proliferation, and increased angiogenesis and metastasis.
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