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EnglishWe have previously shown that whereas T-cells from normal individuals undergo accumulation of p53 and apoptosis when treated with the genotoxic agent Actinomycin D (ActD), those from Ataxia Telangiectasia (AT) and Nijmegen Breakage Syndrome (NBS) patients resist ActD-induced apoptosis [1]. We have now found similar resistance by the p53-null Jurkat T-cell line and by siRNA p53-knockdown normal T-cells. This evidence that ActD initiates a p53-dependent apoptotic responce prompted us to look for defective p53 accumulation by AT and NBS T-cells. Surprisingly the total p53 level was only slightly reduced compared to normal T cells but its intracellular localization was highly defective: p53 was poorly accumulated in the cytosol and nearly undetectable in mitochondria. In accordance with the dependence of ActD-induced apoptosis on a mitochondrial p53 function, in control T-cells specific inhibition of mitochondrial p53 translocation with μ pifithrin reduced apoptosis by 86%, whereas treatment with α pifithrin, which blocks p53-mediated transcription, had no effect. We also showed that nuclear export is not required for mitochondrial p53 translocation. Observation of an altered p53 ubiquitination pattern and Mdm2 accumulation in ActD-treated AT and NBS T-cells provided a mechanistic link to their defective extranuclear p53 localization. Our results disclose an undescribed defect in mitochondrial p53 accumulation in AT and NBS T-cells that makes them resistant to apoptosis following unrepairable DNA damage
| Titolo: | A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells | |
| Autori Riconosciuti: | ||
| Autori: | Turinetto, Valentina; Porcedda, P; Minieri, Valentina; Orlando, Luca; Lantelme, Erica Maria; Accomasso, Lisa; Amoroso, Antonio; DE MARCHI, Mario; Zannini, L; Delia, D; Giachino, Claudia | |
| Data di pubblicazione: | 2010 | |
| Abstract: | We have previously shown that whereas T-cells from normal individuals undergo accumulation of p53 and apoptosis when treated with the genotoxic agent Actinomycin D (ActD), those from Ataxia Telangiectasia (AT) and Nijmegen Breakage Syndrome (NBS) patients resist ActD-induced apoptosis [1]. We have now found similar resistance by the p53-null Jurkat T-cell line and by siRNA p53-knockdown normal T-cells. This evidence that ActD initiates a p53-dependent apoptotic responce prompted us to look for defective p53 accumulation by AT and NBS T-cells. Surprisingly the total p53 level was only slightly reduced compared to normal T cells but its intracellular localization was highly defective: p53 was poorly accumulated in the cytosol and nearly undetectable in mitochondria. In accordance with the dependence of ActD-induced apoptosis on a mitochondrial p53 function, in control T-cells specific inhibition of mitochondrial p53 translocation with μ pifithrin reduced apoptosis by 86%, whereas treatment with α pifithrin, which blocks p53-mediated transcription, had no effect. We also showed that nuclear export is not required for mitochondrial p53 translocation. Observation of an altered p53 ubiquitination pattern and Mdm2 accumulation in ActD-treated AT and NBS T-cells provided a mechanistic link to their defective extranuclear p53 localization. Our results disclose an undescribed defect in mitochondrial p53 accumulation in AT and NBS T-cells that makes them resistant to apoptosis following unrepairable DNA damage | |
| Volume: | 9 | |
| Pagina iniziale: | 1200 | |
| Pagina finale: | 1208 | |
| Digital Object Identifier (DOI): | 10.1016/j.dnarep.2010.09.003 | |
| URL: | http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6X17-517GVV6-2-F&_cdi=7235&_user=525216&_pii=S1568786410003083&_origin=search&_coverDate=10%2F14%2F2010&_sk=999999999&view=c&wchp=dGLbVtz-zSkWb&md5=aaaa42c74fd543be670670171848b656&ie=/sdarticle.pdf | |
| Parole Chiave: | Ataxia Telangiectasia; Nijmegen Breakage Syndrome; p53; Apoptosis; DNA damage | |
| Rivista: | DNA REPAIR | |
| Appare nelle tipologie: | 03A-Articolo su Rivista |
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