MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis.

Simona Nanni, Alfredo Pontecorvi, Antonella Farsetti, Fabiola Moretti, Francesca Gentiletti, Marco D'Angelo, Simona Giglio, Carmen D'Angelo, Gennaro Citro, Ada Sacchi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

34 Citazioni (Scopus)

Abstract

Rescue of embryonic lethality in MDM4-/- mice through concomitant loss of p53 has revealed a functional partnership between the two proteins. Biochemical studies have suggested that MDM4 may act as a negative regulator of p53 levels and activity. On the other hand, MDM4 overexpression has been reported to stabilize p53 levels and to counteract MDM2-degradative activity. We have investigated the functional role of MDM4 overexpression on cell behaviour. In both established and primary cells cultured under stress conditions, overexpression of MDM4 significantly increased p53-dependent cell death, in correlation with enhanced induction of the endogenous p53 protein levels. This phenomenon was associated with induced p53 transcriptional activity and increased levels of the pro-apoptotic protein, Bax. Further, p53 stabilization was accompanied by decreased association of the protein to its negative regulator, MDM2. These findings reveal a novel role for MDM4 by demonstrating that in non-tumor cells under stress conditions it may act as a positive regulator of p53 activity, by mainly controlling p53 levels. They also indicate a major distinction between the biological consequences of MDM4 and MDM2 overexpression
Lingua originaleEnglish
pagine (da-a)8169-8180
Numero di pagine12
RivistaTHE JOURNAL OF BIOLOGICAL CHEMISTRY
Stato di pubblicazionePubblicato - 2004

Keywords

  • apoptosi
  • cancro
  • p53

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