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First published on November 7, 2007; DOI: 10.1124/mol.107.038323

0026-895X/08/7302-498-508$20.00
Mol Pharmacol 73:498-508, 2008

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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

Laura Papucci, Ewa Witort, Anna Maria Bevilacqua, Martino Donnini, Matteo Lulli, Elisabetta Borchi, Khalid S. A. Khabar, Alessio Tempestini, Andrea Lapucci, Nicola Schiavone, Angelo Nicolin, and Sergio Capaccioli

Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy (L.P., E.W., M.D., M.L., E.B., A.T., A.L., N.S., S.C.); Program in Biomolecular Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (K.A.K.); and Department of Pharmacology, University of Milan, Italy (A.M.B, A.N.)

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.

Received May 21, 2007; accepted November 6, 2007

Address correspondence to: Dr. Nicola Schiavone, Department of Experimental Pathology and Oncology, University of Florence, Viale G.B. Morgagni 50, 50134 Florence, Italy. E-mail: nicola{at}unifi.it






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