| A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells. | |
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MedLine Citation:
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PMID: 20947454 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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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. |
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Authors:
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Valentina Turinetto; Paola Porcedda; Valentina Minieri; Luca Orlando; Erica Lantelme; Lisa Accomasso; Antonio Amoroso; Mario De Marchi; Laura Zannini; Domenico Delia; Claudia Giachino |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-14 |
Journal Detail:
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Title: DNA repair Volume: 9 ISSN: 1568-7856 ISO Abbreviation: DNA Repair (Amst.) Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-02 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101139138 Medline TA: DNA Repair (Amst) Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1200-8 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier B.V. All rights reserved. |
Affiliation:
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Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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