RT Journal Article SR Electronic T1 Impact of Targeting the Adenine- and Uracil-Rich Element of bcl-2 mRNA with Oligoribonucleotides on Apoptosis, Cell Cycle, and Neuronal Differentiation in SHSY-5Y Cells JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 498 OP 508 DO 10.1124/mol.107.038323 VO 73 IS 2 A1 Papucci, Laura A1 Witort, Ewa A1 Bevilacqua, Anna Maria A1 Donnini, Martino A1 Lulli, Matteo A1 Borchi, Elisabetta A1 Khabar, Khalid S. A. A1 Tempestini, Alessio A1 Lapucci, Andrea A1 Schiavone, Nicola A1 Nicolin, Angelo A1 Capaccioli, Sergio YR 2008 UL http://molpharm.aspetjournals.org/content/73/2/498.abstract AB We have identified previously a destabilizing adenine- and uracil-rich element (ARE) in the 3′-UTR of bcl-2 mRNA that interacted with ARE-binding proteins to down-regulate bcl-2 gene expression in response to apoptotic stimuli. We have also described three contiguous 2′-O-methyl oligoribonucleotides (ORNs) in both sense and antisense orientation with respect to the bcl-2 ARE that are able to regulate the bcl-2 mRNA half-life and Bcl-2 protein level in two different cell lines. Here we show that treatment of neuronal cell line (SHSY-5Y) with antisense ORNs targeting the bcl-2 ARE (bcl-2 ARE asORNs) prevents bcl-2 down-regulation in response to apoptotic stimuli with glucose/growth factor starvation (Locke medium) or oxygen deprivation and enhances the apoptotic threshold as evaluated by time-lapse videomicroscopy, fluorescence-activated cell sorting analysis, and caspase-3 activation. Additional effects of bcl-2 ARE asORNs included inhibition of cell cycle entry and a marked increase of cellular neurite number and length, a hallmark of neuronal differentiation resulting from bcl-2 up-regulation. The ability of bcl-2 ARE asORNs to enhance the apoptotic threshold and to induce neuronal differentiation implies their potential application as a novel informational tool to protect cells from ischemic damage and to prevent neuronal degeneration. The American Society for Pharmacology and Experimental Therapeutics