Modifications de la protéine p53 et induction de l'apoptose par le NO et ses dérivés : mécanismes réactionnels et implication dans la cancérogenèse

Abstract : The aim of this study is to better understand the role of nitric oxide (NO.) and its derivatives in carcinogenesis. In the first part of this work, we have shown that a treatment by a NO donor, S-nitrosoglutathione (GSNO), induced an accumulation of the tumor suppressor p53 protein but inhibited its DNA binding activity and its anti-proliferative function. We have hypothesized that this alteration of p53 could be due to modification(s)of p53 protein by NO.and its derivatives. We found that NO. (and/or its derivatives) reacted with p53 protein to form nitrotyrosine residues . We have also observed that 1mM GSNO induced apoptosis that was well correlated with the accumulation of the pro-apoptotic protein Bax, one of the target genes of p53. Nevertheless, we have also demonstrated that Bax could accumulate by a p53 independent pathway. Thus, partial inactivation of p53 through overproduction of NO. could occur in inflamed tissues, playing an important role in cell death control and tumor. In the second part of this work, our purpose was to determine chemical reactions that could occur between some reactive species produced during the inflammatory process. We have found that, in vitro, the reaction between nitroxyl aion (NO-) and H2O2, in the presence of metal transition ions, induced the formation of 8-oxo-deoxyguanosine and of malondialhehyde from deoxyribose that was inhibited by radical hydroxyl chelators. We proposed that NO- behaved as a reductor agent to form hydroxyl radical in the presence of H2O2 and ions metallic transition ions. Formation of 8-oxo-deoxyguanosine was also found in MCF-7 cells exposed to NO-/H2O2 and NO./H2O2. Furthermore, these compounds induced rapidly apoptosis, which could be inhibited by the iron chelator deferoxamine, demonstrating the importance of transition metallic ions for the toxicity NO-/H2O2 and NO./H2O2
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Laurence Aubert. Modifications de la protéine p53 et induction de l'apoptose par le NO et ses dérivés : mécanismes réactionnels et implication dans la cancérogenèse. Biochimie, Biologie Moléculaire. Université Paul Verlaine - Metz, 2000. Français. ⟨NNT : 2000METZ032S⟩. ⟨tel-01775389⟩

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