MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response

F. Mancini, Luisa Pieroni, V. Monteleone, R. Lucà, L. Fici, E. Luca, Andrea Urbani, S. Xiong, Silvia Soddu, R. Masetti, G. Lozano, Alfredo Pontecorvi, F. Moretti

Research output: Contribution to journalArticle

Abstract

The p53 inhibitor, MDM4 (MDMX) is a cytoplasmic protein with p53-activating function under DNA damage conditions. Particularly, MDM4 promotes phosphorylation of p53 at Ser46, a modification that precedes different p53 activities. We investigated the mechanism by which MDM4 promotes this p53 modification and its consequences in untransformed mammary epithelial cells and tissues. In response to severe DNA damage, MDM4 stimulates p53Ser46P by binding and stabilizing serine-threonine kinase HIPK2. Under these conditions, the p53-inhibitory complex, MDM4/MDM2, dissociates and this allows MDM4 to promote p53/HIPK2 functional interaction. Comparative proteomic analysis of DNA damage-treated cells versus -untreated cells evidenced a diffuse downregulation of proteins with anti-apoptotic activity, some of which were targets of p53Ser46P/HIPK2 repressive activity. Importantly, MDM4 depletion abolishes the downregulation of these proteins indicating the requirement of MDM4 to promote p53-mediated transcriptional repression. Consistently, MDM4-mediated HIPK2/p53 activation precedes HIPK2/p53 nuclear translocation and activity. Noteworthy, repression of these proteins was evident also in mammary glands of mice subjected to γ-irradiation and was significantly enhanced in transgenic mice overexpressing MDM4. This study evidences the flexibility of MDM2/MDM4 heterodimer, which allows the development of a positive activity of cytoplasmic MDM4 towards p53-mediated transcriptional function. Noteworthy, this activity uncovers coordinated repression of molecules with shared anti-apoptotic function which precedes active cell apoptosis and that are frequently overexpressed and/or markers of tumour phenotype in human cancer.

Original languageEnglish
Pages (from-to)228-240
Number of pages13
JournalOncogene
Volume35
Issue number2
DOIs
Publication statusPublished - Jan 14 2016

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DNA Damage
Down-Regulation
Apoptosis Regulatory Proteins
Proteins
Protein-Serine-Threonine Kinases
Human Mammary Glands
Tumor Biomarkers
Proteomics
Transgenic Mice
Breast
Epithelium
Epithelial Cells
Phosphorylation
Apoptosis
Phenotype
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response. / Mancini, F.; Pieroni, Luisa; Monteleone, V.; Lucà, R.; Fici, L.; Luca, E.; Urbani, Andrea; Xiong, S.; Soddu, Silvia; Masetti, R.; Lozano, G.; Pontecorvi, Alfredo; Moretti, F.

In: Oncogene, Vol. 35, No. 2, 14.01.2016, p. 228-240.

Research output: Contribution to journalArticle

Mancini, F, Pieroni, L, Monteleone, V, Lucà, R, Fici, L, Luca, E, Urbani, A, Xiong, S, Soddu, S, Masetti, R, Lozano, G, Pontecorvi, A & Moretti, F 2016, 'MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response', Oncogene, vol. 35, no. 2, pp. 228-240. https://doi.org/10.1038/onc.2015.76
Mancini, F. ; Pieroni, Luisa ; Monteleone, V. ; Lucà, R. ; Fici, L. ; Luca, E. ; Urbani, Andrea ; Xiong, S. ; Soddu, Silvia ; Masetti, R. ; Lozano, G. ; Pontecorvi, Alfredo ; Moretti, F. / MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response. In: Oncogene. 2016 ; Vol. 35, No. 2. pp. 228-240.
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