Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression

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  • dc.contributor.author Marruecos, Laura
  • dc.contributor.author Manils, Joan
  • dc.contributor.author Moreta, Cristina
  • dc.contributor.author Gómez, Diana
  • dc.contributor.author Filgaira, Ingrid
  • dc.contributor.author Serafín, Anna
  • dc.contributor.author Cañas, Xavier
  • dc.contributor.author Espinosa Blay, Lluís
  • dc.contributor.author Soler Prat, Concepció
  • dc.date.accessioned 2021-09-06T06:58:55Z
  • dc.date.available 2021-09-06T06:58:55Z
  • dc.date.issued 2021
  • dc.description.abstract 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.
  • dc.description.sponsorship This study was supported by research grants from the Ministerio de Economía y Competitividad (BFU2010-15674 and SAF2017-83815R MICIU/AEI/FEDER/UE to C.S.), the Instituto de Salud Carlos III (FEDER PI19/00013 to L.E.), and the Generalitat de Catalunya (2017SGR 1641 and 2017SGR 135). L.M. was supported by FI/AGAUR-15.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Marruecos L, Manils J, Moreta C, Gómez D, Filgaira I, Serafin A, Cañas X, Espinosa L, Soler C. Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression. Cell Death Dis. 2021;12(4):359. DOI: 10.1038/s41419-021-03638-3
  • dc.identifier.doi http://dx.doi.org/10.1038/s41419-021-03638-3
  • dc.identifier.issn 2041-4889
  • dc.identifier.uri http://hdl.handle.net/10230/48392
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Cell Death Dis. 2021;12(4):359
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2010-15674
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-83815R
  • dc.rights © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Chronic inflammation
  • dc.subject.keyword Stress signalling
  • dc.subject.keyword Tumour-suppressor proteins
  • dc.title Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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