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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 34 Issue 19 Pg. 2493-504 (May 07 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 24998848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1beta
• MAFF protein, human
• MafF Transcription Factor
• Nuclear Proteins
• RNA, Small Interfering
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Cell Line, Tumor
• DNA-Binding Proteins (genetics)
• HT29 Cells
• Hep G2 Cells
• Humans
• Inflammation (genetics, immunology)
• Interleukin 1 Receptor Antagonist Protein (antagonists & inhibitors, biosynthesis, genetics)
• Interleukin-1beta (pharmacology)
• MCF-7 Cells
• MafF Transcription Factor (metabolism)
• Mutation
• Neoplasms (genetics, mortality)
• Nuclear Proteins (metabolism)
• Prognosis
• Promoter Regions, Genetic (genetics)
• Protein Binding
• RNA Interference
• RNA, Small Interfering
• Tumor Microenvironment (immunology)
• Tumor Suppressor Protein p53 (genetics)