title: 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.affiliation: Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Ubertini
authors.affiliation: Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Norelli
authors.affiliation: Istituto Dermopatico Dell'immacolata IDI-IRCSS, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: D'Arcangelo
authors.affiliation: Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gurtner
authors.affiliation: Istituto Dermopatico Dell'immacolata IDI-IRCSS, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cesareo
authors.affiliation: Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Baldari
authors.affiliation: Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: M P
authors.initials: MP
authors.lastname: Gentileschi
authors.affiliation: Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.identifier: 0000000321141892
authors.initials: G
authors.lastname: Piaggio
authors.affiliation: Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Nisticò
authors.affiliation: Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Soddu
authors.affiliation: Istituto Dermopatico Dell'immacolata IDI-IRCSS, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Facchiano
authors.affiliation: Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bossi
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology; D061986:MCF-7 Cells; D051260:MafF Transcription Factor / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000401:mortality; D009687:Nuclear Proteins / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D059016:Tumor Microenvironment / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C484147:MAFF protein, human; D051260:MafF Transcription Factor; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53