UC San Diego

The AU-rich element (ARE) is a cis-encoded determinant within mRNA 3' untranslated regions (UTRs) that contributes to mRNA translation and stability in the cell. Tristetraprolin (TTP) is an RNA binding protein that specifically binds to mRNAs containing AREs and activates their rapid decay. TTP is rapidly activated following external stimulus and modulates the gene expression program of the responding cell. To better understand TTP- mediated mRNA decay activity, I identified the RNA binding protein hnRNP F as an RNA-independent interactor of TTP. I further characterized this interaction and observed that hnRNP F stimulated the decay of a subset of TTP-associated mRNAs, thus implicating hnRNP F in mRNA decay activated by TTP. Several possible mechanisms were tested but it remains to be determined how hnRNP F stimulates the decay of TTP-associated mRNAs. In addition to mRNA degradation, TTP appears to regulate gene expression through non-mRNA decay activities. I observed that TTP expression stimulated the 3' end processing of ARE-containing reporter mRNAs, leading to alternatively polyadenylated mRNAs with shortened 3' UTRs. This resulted in stabilization and loss of regulation of these mRNAs by TTP. The 3' end processing required an ARE and an upstream polyadenylation signal, and RNA binding of TTP was necessary but not sufficient for this activity. Thus, TTP appears to be a multifunctional protein, which in addition to mRNA decay activity promotes the 3' end processing of mRNAs, altering the 3' UTR composition and mRNA regulation in cells