Apoptosis of tumoral and nontumoral lymphoid cells is induced by both mdm2and p53 antisense oligodeoxynucleotides

Following stress signals, the p53 tumor suppressor protein plays a critical role in regulation of cell proliferation, mainly through induction of grow th arrest or apoptosis, Therefore, this protein needs to be strictly regula ted and numerous studies have shown that the MDMS protein is an essential e lement for p53 regulation in normal cells and, most importantly, that overe xpression of MDMS is responsible for p53 inactivation in various types of t umors. A previous study showed that this is the case in some Burkitt lympho ma (BL) cell lines, where enhanced translation of mdm2 messenger RNA result s in overexpression of the protein that complexes and inactivates wild-type p53, To further investigate the role of the p53/MDM2 complex in these BL c ells, as well as in other lymphoid cells that do not overexpress MDMS, this study used antisense oligodeoxynucleotides directed either against mdm2 or against p53, Results show that the mdm2 antisense oligodeoxynucleotide ind uces apoptosis of cells that express a high or low level of MDMS protein, o nly if they contain wild-type p53, Moreover, apoptosis is independent of th e accumulation of p53 following mdm2 antisense treatment. Finally, the p53 antisense oligodeoxynucleotide, which inhibits the expression of wildtype p 53, also induces a decrease of the MDMS level in cells, whether or not they overexpress this protein, and causes apoptosis of these cells. These resul ts indicate that decreasing the MDM2 protein level by directly or indirectl y targeting its biosynthesis is a potent tool for the induction of apoptosi s. (C) 2001 by The American Society of Hematology.