Complex regulation of p73 isoforms after alteration of amyloid precursor polypeptide (APP) function and DNA damage in neurons.
Fiche publication
Date publication
décembre 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GAIDDON Christian, Dr GROSS Isabelle, Dr LOEFFLER Jean-Philippe
Tous les auteurs :
Benosman S, Meng X, Von Grabowiecki Y, Palamiuc L, Hritcu L, Gross I, Mellitzer G, Taya Y, Loeffler JP, Gaiddon C
Lien Pubmed
Résumé
Genetic ablations of p73 have shown its implication in the development of the nervous system. However, the relative contribution of DeltaNp73 and TAp73 isoforms in neuronal functions is still unclear. In this study, we have analyzed the expression of these isoforms during neuronal death induced by alteration of the amyloid-beta precursor protein function or cisplatin. We observed a concomitant up-regulation of a TAp73 isoform and a down-regulation of a DeltaNp73 isoform. The shift in favor of the pro-apoptotic isoform correlated with an induction of the p53/p73 target genes such as Noxa. At a functional level, we showed that TAp73 induced neuronal death and that DeltaNp73 has a neuroprotective role toward amyloid-beta precursor protein alteration or cisplatin. We investigated the mechanisms of p73 expression and found that the TAp73 expression was regulated at the promoter level. In contrast, regulation of DeltaNp73 protein levels was regulated by phosphorylation at residue 86 and multiple proteases. Thus, this study indicates that tight transcriptional and post-translational mechanisms regulate the p73 isoform ratios that play an important role in neuronal survival.
Référence
J Biol Chem. 2011 Dec 16;286(50):43013-25