The roles of TTP and BRF proteins in regulated mRNA decay

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.