PMID- 33824284
OWN - NLM
STAT- MEDLINE
DCOM- 20210920
LR  - 20210920
IS  - 2041-4889 (Electronic)
VI  - 12
IP  - 4
DP  - 2021 Apr 6
TI  - Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and 
      cytokine inflammatory responses through deregulation of IkappaBalpha expression.
PG  - 359
LID - 10.1038/s41419-021-03638-3 [doi]
LID - 359
AB  - 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), TNFalpha (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-kappaB pathway inhibitor IkappaBalpha. 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-kappaB 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.
FAU - Marruecos, Laura
AU  - Marruecos L
AD  - Cancer Research Program, CIBERONC Institut Hospital del Mar d'Investigacions 
      Mediques (IMIM), Barcelona, Spain.
FAU - Manils, Joan
AU  - Manils J
AD  - Unitat d'Immunologia, Departament de Patologia i Terapeutica Experimental, 
      Facultat de Medicina i Ciencies de la Salut, Institut de Neurociencies, 
      Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
AD  - Department of Immunology & Inflammation, Imperial College London, London, United 
      Kingdom.
FAU - Moreta, Cristina
AU  - Moreta C
AD  - Unitat d'Immunologia, Departament de Patologia i Terapeutica Experimental, 
      Facultat de Medicina i Ciencies de la Salut, Institut de Neurociencies, 
      Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
FAU - Gomez, Diana
AU  - Gomez D
AD  - Unitat d'Immunologia, Departament de Patologia i Terapeutica Experimental, 
      Facultat de Medicina i Ciencies de la Salut, Institut de Neurociencies, 
      Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
FAU - Filgaira, Ingrid
AU  - Filgaira I
AUID- ORCID: 0000-0002-9886-3925
AD  - Unitat d'Immunologia, Departament de Patologia i Terapeutica Experimental, 
      Facultat de Medicina i Ciencies de la Salut, Institut de Neurociencies, 
      Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
FAU - Serafin, Anna
AU  - Serafin A
AD  - PCB Animal Facility, Parc Cientific de Barcelona, Barcelona, Spain.
FAU - Canas, Xavier
AU  - Canas X
AD  - Vall d'Hebron Institute of Research, Barcelona, Spain.
FAU - Espinosa, Lluis
AU  - Espinosa L
AUID- ORCID: 0000-0002-2897-4099
AD  - Cancer Research Program, CIBERONC Institut Hospital del Mar d'Investigacions 
      Mediques (IMIM), Barcelona, Spain.
FAU - Soler, Concepcio
AU  - Soler C
AUID- ORCID: 0000-0001-6502-5012
AD  - Unitat d'Immunologia, Departament de Patologia i Terapeutica Experimental, 
      Facultat de Medicina i Ciencies de la Salut, Institut de Neurociencies, 
      Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. 
      concepciosoler@ub.edu.
AD  - Neuropharmacology & Pain Group, Neuroscience Program, Institut d'Investigacio 
      Biomedica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain. 
      concepciosoler@ub.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210406
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Cytokines)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
SB  - IM
MH  - Animals
MH  - Carcinogenesis/genetics
MH  - Cytokines/*genetics/metabolism
MH  - DNA Damage/*genetics
MH  - Gene Expression/genetics
MH  - Genomic Instability/genetics
MH  - I-kappa B Proteins/*metabolism
MH  - Inflammation/*genetics
MH  - Loss of Heterozygosity/*genetics
MH  - Lymphoma/genetics
MH  - Mice, Transgenic
MH  - NF-KappaB Inhibitor alpha/genetics
MH  - Tumor Suppressor Protein p53/*genetics/metabolism
PMC - PMC8024389
COIS- The authors declare no competing interests.
EDAT- 2021/04/08 06:00
MHDA- 2021/09/21 06:00
PMCR- 2021/04/06
CRDT- 2021/04/07 06:01
PHST- 2020/09/05 00:00 [received]
PHST- 2021/03/16 00:00 [accepted]
PHST- 2021/03/12 00:00 [revised]
PHST- 2021/04/07 06:01 [entrez]
PHST- 2021/04/08 06:00 [pubmed]
PHST- 2021/09/21 06:00 [medline]
PHST- 2021/04/06 00:00 [pmc-release]
AID - 10.1038/s41419-021-03638-3 [pii]
AID - 3638 [pii]
AID - 10.1038/s41419-021-03638-3 [doi]
PST - epublish
SO  - Cell Death Dis. 2021 Apr 6;12(4):359. doi: 10.1038/s41419-021-03638-3.