Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression
| Autor: | Xavier Cañas, Diana Gómez, Laura Marruecos, Lluis Espinosa, Concepció Soler, Joan Manils, Anna Serafín, Cristina Moreta, Ingrid Filgaira |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Lymphoma DNA damage Carcinogenesis medicine.medical_treatment Immunology Gene Expression Loss of Heterozygosity Mice Transgenic Biology medicine.disease_cause Oxidació Article Genomic Instability 03 medical and health sciences Cellular and Molecular Neuroscience Stress signalling 0302 clinical medicine NF-KappaB Inhibitor alpha Citoquines Oxidation medicine Animals Allele lcsh:QH573-671 Tumour-suppressor proteins Inflammation lcsh:Cytology Cell Biology Chronic inflammation Inflamació IκBα 030104 developmental biology Cytokine 030220 oncology & carcinogenesis Cancer research Cytokines Tumor necrosis factor alpha I-kappa B Proteins Tumor Suppressor Protein p53 Chromatin immunoprecipitation Oxidative stress DNA Damage |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Cell Death and Disease, Vol 12, Iss 4, Pp 1-15 (2021) Cell Death & Disease |
| Popis: | Dose of Trp53, the main keeper of genome stability, influences tumorigenesis; however, the causes underlying and driving tumorigenesis over time by the loss of a single p53 allele are still poorly characterized. Here, we found that single p53 allele loss specifically impacted the oxidative, DNA damage and inflammatory status of hematopoietic lineages. In particular, single Trp53 allele loss in mice triggered oxidative stress in peripheral blood granulocytes and spleenocytes, whereas lack of two Trp53 alleles produced enhanced oxidative stress in thymus cells, resulting in a higher incidence of lymphomas in the Trp53 knockout (KO) mice compared with hemizygous (HEM). In addition, single or complete loss of Trp53 alleles, as well as p53 downregulation, led to a differential increase in basal, LPS- and UVB-induced expression of a plethora of pro-inflammatory cytokine, such as interleukin-12 (Il-12a), TNFα (Tnfa) and interleukin (Il-23a) in bone marrow-derived macrophage cells (BMDMs) compared to WT cells. Interestingly, p53-dependent increased inflammatory gene expression correlated with deregulated expression of the NF-κB pathway inhibitor IκBα. Chromatin immunoprecipitation data revealed decreased p65 binding to Nfkbia in the absence of p53 and p53 binding to Nfkbia promoter, uncovering a novel crosstalk mechanism between p53 and NF-κB transcription factors. Overall, our data suggest that single Trp53 allele loss can drive a sustained inflammatory, DNA damage and oxidative stress response that, over time, facilitate and support carcinogenesis. |
| Databáze: | OpenAIRE |
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