Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy

Alfredo Pontecorvi, Marsha Pellegrino, Francesca Mancini, Laura Fici, Fabiola Moretti, Rossella Lucà, Alice Coletti, Nicola Giacchè, Isabella Manni, Ivan Arisi, Fulvio Florenzano, Marianna Buttarelli, Rossella Brandi, Tiziana Bruno, Maurizio Fanciulli, Mara D'Onofrio, Giulia Piaggio, Roberto Pellicciari, Jean Christophe Marine, Antonio Macchiarulo

Risultato della ricerca: Contributo in rivistaArticolo in rivista

25 Citazioni (Scopus)

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. Cancer Res; 75(21); 4560-72. ©2015 AACR.
Lingua originaleEnglish
pagine (da-a)4560-4572
Numero di pagine13
RivistaCancer Research
Volume75
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • p53

Fingerprint Entra nei temi di ricerca di 'Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy'. Insieme formano una fingerprint unica.

Cita questo