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Bristot 2014 Abstract MiP2014
Additional label MiP2014  +
Coupling states LEAK  + , OXPHOS  +
Diseases Cancer  +
Event C1  + , Oral  +
Has abstract Li-Fraumeni Syndrome (LFS) and Li-Fraumeni
Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like Syndrome (LFL) are inherited disorders, associated to TP53 germline mutations and characterized by increased predisposition to multiple early-onset cancers [1]. Studies in families from Southern and Southeastern Brazil with LFS/LFL phenotype have identified a germline founder mutation in the TP53 gene, the p.R337H mutation (c.1010G>A), in a high population prevalence (~0.3%) [2]. Unlike the majority of the mutations in TP53, which are missense mutations located in the DNA-binding domain (DBD) of the protein (exons 5-8), the TP53 p.R337H (c.1010G>A) is located in exon 10, corresponding to the oligomerization domain (OD). The p53 nuclear phosphoprotein is known for its functions in the DNA damage response and apoptosis. Recently, this protein has been shown to regulate many aspects of energy metabolism as well as enzymes that are involved in cell responses to oxidative stress, manly through TIGAR activation [3]. In a previous work, we analyzed the levels of several markers of oxidative stress responses in blood samples of p.R337H mutation carries and non-carries. We observed oxidative damage in lipids and proteins. Moreover, there was increased erythrocyte GPx activity, as well as increased total antioxidant status in the p.R337H mutation carries [4]. Therefore, our study was able to establish the relationship of oxidative stress with the loss of function of p53. The aim of this work was to evaluate the association between TP53 germline mutations with deregulation of cell bioenergetics. For this purpose, we performed high-resolution respirometry (HHR) of intact human fibroblast cells, derived from patients. Preliminary results showed a distinct pattern of HHR in different TP53 germline mutations genotypes. Fibroblasts from carriers of DBD mutations and wt/p.R337H showed higher ROUTINE, total and extramitochodrial respiration, as well as LEAK respiration, compared to p.R377H/p.R337H mutants and WT/WT cells. In agreement with HHR results, cells with DBD mutation showed increased ROS (reactive oxygen species) by DCF assay. On the other hand an unexpectedly high production was found of ROS by p.R377H/p.R337H. These data were correlated with antimetabolic drug sensitivity, mitochondrial membrane potential and cellular doubling time to better evaluate the potential role of these findings for the increased predisposition to multiple early-onset cancers presented by Li-Fraumeni patients.
cancers presented by Li-Fraumeni patients.  +
Has title High-resolution respirometry and bioenergetics evaluation in fibroblasts derived from patients with TP53 germline mutations.  +
Instrument and method Oxygraph-2k  +
Mammal and model Human  +
MiP area Respiration  + , nDNA;cell genetics  + , mt-Medicine  +
Preparation Intact cells  +
Stress Oxidative stress;RONS  +
Tissue and cell Fibroblast  +
Was published by MiPNetLab BR Porto Alegre Klamt F +
Was submitted in year 2014  +
Was submitted to event MiP2014 +
Was written by Bristot IJ + , Macedo G + , Neto CB + , Ashton-Prolla P + , Klamt F +
Categories Abstracts
Modification date
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13:27:11, 9 November 2016  +
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