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

Oncogene volume 34, pages 2493–2504 (2015)Cite this article

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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.

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Acknowledgements

We thank Dr S Bacchetti, Dr FL Graham and Dr G D’Orazi for critical reading of the manuscript; Dr C Gabay for providing pRa-1680-Luc vector; and Dr G Tolstonog for ENCODE in silico analyses on the sIL-1Ra promoter. This work was supported with grants from Associazione Italiana Ricerca sul Cancro (AICR) to GB (IG no. 8804), AG (MFAG no. 11752), PG (IG no. 13234), and AF (RC 3.5–2013). We thank the Proteomic Facility for Complex Potein Muxture (CPM) Analisys at ISS, Rome.

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Authors and Affiliations

  1. Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy

    V Ubertini, G Norelli, A Gurtner, S Baldari, M P Gentileschi, G Piaggio, P Nisticò & S Soddu

  2. Istituto Dermopatico Dell’immacolata IDI-IRCSS, Rome, Italy

    D D'Arcangelo, E Cesareo & A Facchiano

  3. Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy

    G Bossi

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Ubertini, V., Norelli, G., D'Arcangelo, D. et al. Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist. Oncogene 34, 2493–2504 (2015). https://doi.org/10.1038/onc.2014.191

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