LIM only domain protein 4 (LMO4) interacts with many signaling and transcription factors to regulate cellular proliferation, differentiation and plasticity. In Drosophila, mutations in the 3' untranslated region (UTR) of the homologue dLMO cause a gain of function by increasing mRNA stability. LMO4 3'UTR contains several AU-rich elements (ARE) and is highly conserved among vertebrates, suggesting that RNA destabilizing mechanisms are evolutionarily conserved. Here, we found that extracellular ATP stabilized LMO4 mRNA in F11 cells. The LMO4 3'UTR added to a luciferase reporter markedly reduced reporter activity under basal conditions, but increased activity with ATP treatment. Two ARE motifs were characterized in the LMO4 3'UTR. ATP increased binding of HuD protein to ARE1. ARE1 conferred ATP and HuD-dependent mRNA stabilization. In contrast, sequences flanking ARE2 bound CUGBP1 and ATP destabilized this complex. Thus, our results suggest that ATP modulates recruitment of RNA-binding proteins to the 3'UTR to stabilize LMO4 mRNA. Crown copyright (c) 2007 Published by Elsevier Inc. All rights reserved.