Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy.
Cancer Res
; 75(21): 4560-72, 2015 Nov 01.
Article
en En
| MEDLINE
| ID: mdl-26359458
ABSTRACT
Restoration of wild-type p53 tumor suppressor function has emerged as an attractive anticancer strategy. Therapeutics targeting the two p53-negative regulators, MDM2 and MDM4, have been developed, but most agents selectively target the ability of only one of these molecules to interact with p53, leaving the other free to operate. Therefore, we developed a method that targets the activity of MDM2 and MDM4 simultaneously based on recent studies indicating that formation of MDM2/MDM4 heterodimer complexes are required for efficient inactivation of p53 function. Using computational and mutagenesis analyses of the heterodimer binding interface, we identified a peptide that mimics the MDM4 C-terminus, competes with endogenous MDM4 for MDM2 binding, and activates p53 function. This peptide induces p53-dependent apoptosis in vitro and reduces tumor growth in vivo. Interestingly, interfering with the MDM2/MDM4 heterodimer specifically activates a p53-dependent oxidative stress response. Consistently, distinct subcellular pools of MDM2/MDM4 complexes were differentially sensitive to the peptide; nuclear MDM2/MDM4 complexes were particularly highly susceptible to the peptide-displacement activity. Taken together, these data identify the MDM2/MDM4 interaction interface as a valuable molecular target for therapeutic reactivation of p53 oncosuppressive function.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos
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Proteínas Nucleares
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Proteína p53 Supresora de Tumor
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Proteínas Proto-Oncogénicas
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Proteínas Proto-Oncogénicas c-mdm2
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Terapia Molecular Dirigida
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Neoplasias
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cancer Res
Año:
2015
Tipo del documento:
Article
País de afiliación:
Italia