Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist

V. Ubertini, G. Norelli, D. D'Arcangelo, A. Gurtner, E. Cesareo, S. Baldari, M. P. Gentileschi, G. Piaggio, P. Nisticò, S. Soddu, A. Facchiano, G. Bossi

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The TP53 tumor-suppressor gene is frequently mutated in human cancer. Missense mutations can add novel functions (gain-of-function, GOF) that promote tumor malignancy. Here we report that mutant (mut) p53 promotes tumor malignancy by suppressing the expression of a natural occurring anti-inflammatory cytokine, the secreted interleukin-1 receptor antagonist (sIL-1Ra, IL1RN). We show that mutp53 but not wild-type (wt) p53 suppresses the sIL-1Ra production in conditioned media of cancer cells. Moreover, mutp53, but not wtp53, binds physically the sIL-1Ra promoter and the protein-protein interaction with the transcriptional co-repressor MAFF (v-MAF musculoaponeurotic fibrosarcoma oncogene family, protein F) is required for mutp53-induced sIL-1Ra suppression. Remarkably, when exposed to IL-1 beta (IL-1β) inflammatory stimuli, mutp53 sustains a ready-to-be-activated in vitro and in vivo cancer cells' response through the sIL-1Ra repression. Taken together, these results identify sIL-1Ra as a novel mutp53 target gene, whose suppression might be required to generate a chronic pro-inflammatory tumor microenvironment through which mutp53 promotes tumor malignancy.

Original languageEnglish
Pages (from-to)2493-2504
Number of pages12
JournalOncogene
Volume34
Issue number19
DOIs
Publication statusPublished - May 7 2015

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Interleukin-1 Receptors
Neoplasms
Co-Repressor Proteins
Tumor Microenvironment
Fibrosarcoma
Oncogene Proteins
Missense Mutation
Conditioned Culture Medium
Tumor Suppressor Genes
Interleukin-1beta
Interleukin-1
Proteins
Anti-Inflammatory Agents
Cytokines

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist. / Ubertini, V.; Norelli, G.; D'Arcangelo, D.; Gurtner, A.; Cesareo, E.; Baldari, S.; Gentileschi, M. P.; Piaggio, G.; Nisticò, P.; Soddu, S.; Facchiano, A.; Bossi, G.

In: Oncogene, Vol. 34, No. 19, 07.05.2015, p. 2493-2504.

Research output: Contribution to journalArticle

Ubertini, V. ; Norelli, G. ; D'Arcangelo, D. ; Gurtner, A. ; Cesareo, E. ; Baldari, S. ; Gentileschi, M. P. ; Piaggio, G. ; Nisticò, P. ; Soddu, S. ; Facchiano, A. ; Bossi, G. / Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist. In: Oncogene. 2015 ; Vol. 34, No. 19. pp. 2493-2504.
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