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<p>The Tristetraprolin (TTP) protein family includes four mammalian members (TTP, TIS11b, TIS11d, and ZFP36L3), but only one in <i>Drosophila melanogaster</i> (DTIS11). These proteins bind target mRNAs with AU-rich elements (AREs) <i>via</i> two C3H zinc finger domains and destabilize the mRNAs. We found that overexpression of mouse TIS11b or DTIS11 in the <i>Drosophila</i> retina dramatically reduced eye size, similar to the phenotype of <i>eyes absent</i> (<i>eya</i>) mutants. The <i>eya</i> transcript is one of many ARE-containing mRNAs in <i>Drosophila</i>. We showed that TIS11b reduced levels of <i>eya</i> mRNA <i>in vivo</i>. In addition, overexpression of Eya rescued the TIS11b overexpression phenotype. RNA pull-down and luciferase reporter analyses demonstrated that the DTIS11 RNA-binding domain is required for DTIS11 to bind the <i>eya</i> 3&#8242; UTR and reduce levels of <i>eya</i> mRNA. Moreover, ectopic expression of DTIS11 in <i>Drosophila</i> S2 cells decreased levels of <i>eya </i>mRNA and reduced cell viability. Consistent with these results, TTP proteins overexpressed in MCF7 human breast cancer cells were associated with <i>eya homologue 2</i> (<i>EYA2</i>) mRNA, and caused a decrease in <i>EYA2 </i>mRNA stability and cell viability. Our results suggest that <i>eya </i>mRNA is a target of TTP proteins, and that downregulation of EYA by TTP may lead to reduced cell viability in <i>Drosophila</i> and human cells.</p>