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Blood, 15 February 2001, Vol. 97, No. 4, pp. 1043-1049
NEOPLASIA
Apoptosis of tumoral and nontumoral lymphoid cells is induced by
both mdm2 and p53 antisense oligodeoxynucleotides
Corinne Capoulade,
Lluis M. Mir,
Karine Carlier,
Yann Lécluse,
Cécile Tétaud,
Zohair Mishal, and
Joëlle Wiels
From the CNRS UMR 1598, Interactions moléculaires
et cancer, Institut Gustave Roussy, Villejuif, France; Laboratoire de
cytométrie, Institut de recherche sur le cancer, rue Guy Moquet,
Villejuif, France; CNRS UMR 8532, Physicochimie et pharmacologie des
macromolécules biologiques, Institut Gustave Roussy, Villejuif,
France.
Following stress signals, the p53 tumor suppressor protein plays a
critical role in regulation of cell proliferation, mainly through
induction of growth arrest or apoptosis. Therefore, this protein needs
to be strictly regulated and numerous studies have shown that the MDM2
protein is an essential element for p53 regulation in normal cells and,
most importantly, that overexpression of MDM2 is responsible for p53
inactivation in various types of tumors. A previous study showed that
this is the case in some Burkitt lymphoma (BL) cell lines, where
enhanced translation of mdm2 messenger RNA results 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 cells, as well
as in other lymphoid cells that do not overexpress MDM2, this study
used antisense oligodeoxynucleotides directed either against mdm2 or
against p53. Results show that the mdm2 antisense oligodeoxynucleotide induces apoptosis of cells that express a high or low level of MDM2
protein, only if they contain wild-type p53. Moreover, apoptosis is
independent of the accumulation of p53 following mdm2 antisense treatment. Finally, the p53 antisense oligodeoxynucleotide, which inhibits the expression of wild-type p53, also induces a decrease of
the MDM2 level in cells, whether or not they overexpress this protein,
and causes apoptosis of these cells. These results indicate that
decreasing the MDM2 protein level by directly or indirectly targeting
its biosynthesis is a potent tool for the induction of apoptosis.
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