Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy

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

Research output: Contribution to journalArticle

20 Citations (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 thatmimics theMDM4 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.

Original languageEnglish
Pages (from-to)4560-4572
Number of pages13
JournalCancer Research
Volume75
Issue number21
DOIs
Publication statusPublished - Nov 1 2015

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Peptides
Therapeutics
Mutagenesis
Neoplasms
Oxidative Stress
Apoptosis
Growth
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Pellegrino, M., Mancini, F., Lucà, R., Coletti, A., Giacchè, N., Manni, I., ... Moretti, F. (2015). Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. Cancer Research, 75(21), 4560-4572. https://doi.org/10.1158/0008-5472.CAN-15-0439

Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. / Pellegrino, Marsha; Mancini, Francesca; Lucà, Rossella; Coletti, Alice; Giacchè, Nicola; Manni, Isabella; Arisi, Ivan; Florenzano, Fulvio; Teveroni, Emanuela; Buttarelli, Marianna; Fici, Laura; Brandi, Rossella; Bruno, Tiziana; Fanciulli, Maurizio; D'Onofrio, Mara; Piaggio, Giulia; Pellicciari, Roberto; Pontecorvi, Alfredo; Marine, Jean Christophe; Macchiarulo, Antonio; Moretti, Fabiola.

In: Cancer Research, Vol. 75, No. 21, 01.11.2015, p. 4560-4572.

Research output: Contribution to journalArticle

Pellegrino, M, Mancini, F, Lucà, R, Coletti, A, Giacchè, N, Manni, I, Arisi, I, Florenzano, F, Teveroni, E, Buttarelli, M, Fici, L, Brandi, R, Bruno, T, Fanciulli, M, D'Onofrio, M, Piaggio, G, Pellicciari, R, Pontecorvi, A, Marine, JC, Macchiarulo, A & Moretti, F 2015, 'Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy', Cancer Research, vol. 75, no. 21, pp. 4560-4572. https://doi.org/10.1158/0008-5472.CAN-15-0439
Pellegrino, Marsha ; Mancini, Francesca ; Lucà, Rossella ; Coletti, Alice ; Giacchè, Nicola ; Manni, Isabella ; Arisi, Ivan ; Florenzano, Fulvio ; Teveroni, Emanuela ; Buttarelli, Marianna ; Fici, Laura ; Brandi, Rossella ; Bruno, Tiziana ; Fanciulli, Maurizio ; D'Onofrio, Mara ; Piaggio, Giulia ; Pellicciari, Roberto ; Pontecorvi, Alfredo ; Marine, Jean Christophe ; Macchiarulo, Antonio ; Moretti, Fabiola. / Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. In: Cancer Research. 2015 ; Vol. 75, No. 21. pp. 4560-4572.
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AU - Giacchè, Nicola

AU - Manni, Isabella

AU - Arisi, Ivan

AU - Florenzano, Fulvio

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AU - Fici, Laura

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AU - Piaggio, Giulia

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AU - Macchiarulo, Antonio

AU - Moretti, Fabiola

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