Journal
ONCOGENE
Volume 34, Issue 19, Pages 2493-2504Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2014.191
Keywords
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Funding
- Associazione Italiana Ricerca sul Cancro (AICR) (IG) [8804, 13234]
- Associazione Italiana Ricerca sul Cancro (AICR) (MFAG) [11752]
- Associazione Italiana Ricerca sul Cancro (AICR) (RC) [3.5-2013]
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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 corepressor 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-1 beta) 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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