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Increased Oxidative Damage in Carriers of the Germline TP53 p.R337H Mutation (Oxidative Damage in TP53 p.R337H Carriers)

Macedo, Gabriel S ; Lisbôa da Motta, Leonardo ; Giacomazzi, Juliana ; Netto, Cristina B. O ; Manfredini, Vanusa ; S.Vanzin, Camila ; Vargas, Carmen Regla ; Hainaut, Pierre ; Klamt, Fábio ; Ashton-Prolla, Patricia Deb, Sumitra (Editor)

2012, Vol.7(10), p.e47010 [Periódico revisado por pares]

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  • Título:
    Increased Oxidative Damage in Carriers of the Germline TP53 p.R337H Mutation (Oxidative Damage in TP53 p.R337H Carriers)
  • Autor: Macedo, Gabriel S ; Lisbôa da Motta, Leonardo ; Giacomazzi, Juliana ; Netto, Cristina B. O ; Manfredini, Vanusa ; S.Vanzin, Camila ; Vargas, Carmen Regla ; Hainaut, Pierre ; Klamt, Fábio ; Ashton-Prolla, Patricia
  • Deb, Sumitra (Editor)
  • Assuntos: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Oncology ; Biochemistry
  • É parte de: 2012, Vol.7(10), p.e47010
  • Descrição: Germline mutations in TP53 are the underlying defect of Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders characterized by predisposition to multiple early onset cancers. In Brazil, a variant form of LFS/LFL is commonly detected because of the high prevalence of a founder mutation at codon 337 in TP53 (p.R337H). The p53 protein exerts multiple roles in the regulation of oxidative metabolism and cellular anti-oxidant defense systems. Herein, we analyzed the redox parameters in blood samples from p.R337H mutation carriers (C, n = 17) and non-carriers (NC, n = 17). We identified a significant increase in erythrocyte GPx activity and in plasma carbonyl content,an indicator of protein oxidative damage, in mutation carriers compared to non-carriers ( P  = 0.048 and P  = 0.035, respectively). Mutation carriers also showed a four-fold increase in plasma malondialdehyde levels, indicating increased lipid peroxidation (NC = 40.20±0.71, C = 160.5±0.88, P <0.0001). Finally, carriers showed increased total antioxidant status but a decrease in plasma ascorbic acid content. The observed imbalance could be associated with deregulated cell bioenergetics and/or with increased inflammatory stress, two effects that may result from loss of wild-type p53 function. These findings provide the first evidence that oxidative damage occurs in carriers of a germline TP53 mutation, and these may have important implications regarding our understanding of the mechanisms responsible for germline TP53 p.R337H mutation-associated carcinogenesis.
  • Idioma: Inglês

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