title: Transcriptomic analysis reveals sex-specific differences in the expression of Dcl1 and Fis1 genes in the radio-adaptive response of thymocytes to TRP53-mediated apoptosis.
abstract: Radio-Adaptive Response (RAR) is a biological defense mechanism whereby exposure to low dose ionizing radiation (IR) mitigates the detrimental effects of high dose irradiation. RAR has been widely observed in vivo using as endpoint less induction of apoptosis. However, sex differences associated with RAR and variations between males and females on global gene expression influenced by RAR have not been still investigated. In addition, the response to radiation-induced apoptosis is associated with phosphorylation of TRP53 at both the serine 15 (ser-18 in the mouse) and serine 392 (ser-389 in mice) residues, but the role of these two phosphorylated forms in male and female RAR remains to be elucidated.
  
  
  
  We analyzed the effect of administering priming low dose radiation (0.075 Gy of X-rays) prior to high dose radiation (1.75 Gy of γ-rays) on the level of caspase-3-mediated apoptosis and on global transcriptional expression in thymocytes of male and female mice. Here, we provide the first evidence of a differential sex effect of RAR on the reduction of thymocyte apoptosis with males showing lesser levels of caspase-3-mediated apoptosis than females. Analysis of transcriptomic profiles of 1944 genes involved in apoptosis signaling in radio-adapted thymocytes identified 17 transcripts exhibiting differential expression between both sexes. Among them, Dlc1 and Fis1 are closely related to the apoptosis mediated by the TRP53 protein. Our data demonstrate that overexpression of Dlc1 and Fis1 occur concomitantly with a highest accumulation of phosphoserine-18-TRP53 and caspase-3 in radio-adapted thymocytes of female mice. In an opposite way, both down-modulation of Fis1 and phosphoserine-389-TRP53 accumulation appear to be associated with protection from thymocyte apoptosis mediated by caspase-3 in males.
  
  
  
  Transcriptomic analysis performed in this work reveals for the first time sex-specific differences in gene expression influenced by RAR. Our results also suggest a sex-dependent dual role for phosphoserine-18-TRP53 and phosphoserine-389-TRP53 in the regulation of the radio-adaptive response in mouse thymocytes.
authors: Department of Cellular Biology and Immunology, Severo Ochoa Molecular Biology Center, Madrid Autonomous University (CBMSO-UAM), 28049, Madrid, Spain.|Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain.
authors: Pilar
authors: P
authors: López-Nieva
authors: Department of Cellular Biology and Immunology, Severo Ochoa Molecular Biology Center, Madrid Autonomous University (CBMSO-UAM), 28049, Madrid, Spain.|Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain.
authors: Manuel
authors: M
authors: Malavé
authors: Department of Cellular Biology and Immunology, Severo Ochoa Molecular Biology Center, Madrid Autonomous University (CBMSO-UAM), 28049, Madrid, Spain.|Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain.|Consortium for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain.
authors: Laura
authors: L
authors: González-Sánchez
authors: Department of Cellular Biology and Immunology, Severo Ochoa Molecular Biology Center, Madrid Autonomous University (CBMSO-UAM), 28049, Madrid, Spain. jfpiqueras@cbm.csic.es.|Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain. jfpiqueras@cbm.csic.es.|Consortium for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain. jfpiqueras@cbm.csic.es.|Carlos III Institute of Health, 28029, Madrid, Spain. jfpiqueras@cbm.csic.es.
authors: José
authors: J
authors: Fernández-Piqueras
authors: Cancer and Environmental Epidemiology Unit, National Center for Epidemiology, Carlos III Institute of Health, Madrid, 28029, Spain. pfernandezn@isciii.es.|Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain. pfernandezn@isciii.es.
authors: Pablo
authors: P
authors: Fernández-Navarro
authors: Department of Cellular Biology and Immunology, Severo Ochoa Molecular Biology Center, Madrid Autonomous University (CBMSO-UAM), 28049, Madrid, Spain. javier.santos@uam.es.|Institute of Health Research, Jiménez Díaz Foundation, 28040, Madrid, Spain. javier.santos@uam.es.|Consortium for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain. javier.santos@uam.es.|Carlos III Institute of Health, 28029, Madrid, Spain. javier.santos@uam.es.
authors: Javier
authors: J
authors: Santos
mesh_terms: D000222:Adaptation, Physiological / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000528:radiation effects; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010766:Phosphorylation; D012727:Sex Characteristics; D060168:Thymocytes / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C470572:Dcl1 protein, mouse; C561064:FIS1 protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016159:Tumor Suppressor Protein p53; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Caspase-3; Dlc1; Fis1; Phosphorylation of TRP53 at serine 18 and serine 389; Radio-adaptive response; Sex differences; Thymocyte apoptosis; cDNA microarrays