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Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner
Chemotherapy and radiation, the two most common cancer therapies, exert their anticancer effects by causing damage to cellular DNA. However, systemic treatment damages DNA not only in cancer, but also in healthy cells, resulting in the progression of serious side effects and limiting efficacy of the...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520489/ https://www.ncbi.nlm.nih.gov/pubmed/28394357 http://dx.doi.org/10.1038/oncsis.2017.12 |
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author | Wamsley, J J Gary, C Biktasova, A Hajek, M Bellinger, G Virk, R Issaeva, N Yarbrough, W G |
author_facet | Wamsley, J J Gary, C Biktasova, A Hajek, M Bellinger, G Virk, R Issaeva, N Yarbrough, W G |
author_sort | Wamsley, J J |
collection | PubMed |
description | Chemotherapy and radiation, the two most common cancer therapies, exert their anticancer effects by causing damage to cellular DNA. However, systemic treatment damages DNA not only in cancer, but also in healthy cells, resulting in the progression of serious side effects and limiting efficacy of the treatment. Interestingly, in response to DNA damage, p53 seems to play an opposite role in normal and in the majority of cancer cells—wild-type p53 mediates apoptosis in healthy tissues, attributing to the side effects, whereas mutant p53 often is responsible for acquired cancer resistance to the treatment. Here, we show that leucine zipper-containing ARF-binding protein (LZAP) binds and stabilizes p53. LZAP depletion eliminates p53 protein independently of its mutation status, subsequently protecting wild-type p53 cells from DNA damage-induced cell death, while rendering cells expressing mutant p53 more sensitive to the treatment. In human non-small-cell lung cancer, LZAP levels correlated with p53 levels, suggesting that loss of LZAP may represent a novel mechanism of p53 inactivation in human cancer. Our studies establish LZAP as a p53 regulator and p53-dependent determinative of cell fate in response to DNA damaging treatment. |
format | Online Article Text |
id | pubmed-5520489 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-55204892017-07-28 Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner Wamsley, J J Gary, C Biktasova, A Hajek, M Bellinger, G Virk, R Issaeva, N Yarbrough, W G Oncogenesis Original Article Chemotherapy and radiation, the two most common cancer therapies, exert their anticancer effects by causing damage to cellular DNA. However, systemic treatment damages DNA not only in cancer, but also in healthy cells, resulting in the progression of serious side effects and limiting efficacy of the treatment. Interestingly, in response to DNA damage, p53 seems to play an opposite role in normal and in the majority of cancer cells—wild-type p53 mediates apoptosis in healthy tissues, attributing to the side effects, whereas mutant p53 often is responsible for acquired cancer resistance to the treatment. Here, we show that leucine zipper-containing ARF-binding protein (LZAP) binds and stabilizes p53. LZAP depletion eliminates p53 protein independently of its mutation status, subsequently protecting wild-type p53 cells from DNA damage-induced cell death, while rendering cells expressing mutant p53 more sensitive to the treatment. In human non-small-cell lung cancer, LZAP levels correlated with p53 levels, suggesting that loss of LZAP may represent a novel mechanism of p53 inactivation in human cancer. Our studies establish LZAP as a p53 regulator and p53-dependent determinative of cell fate in response to DNA damaging treatment. Nature Publishing Group 2017-04 2017-04-10 /pmc/articles/PMC5520489/ /pubmed/28394357 http://dx.doi.org/10.1038/oncsis.2017.12 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Wamsley, J J Gary, C Biktasova, A Hajek, M Bellinger, G Virk, R Issaeva, N Yarbrough, W G Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner |
title | Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner |
title_full | Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner |
title_fullStr | Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner |
title_full_unstemmed | Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner |
title_short | Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner |
title_sort | loss of lzap inactivates p53 and regulates sensitivity of cells to dna damage in a p53-dependent manner |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520489/ https://www.ncbi.nlm.nih.gov/pubmed/28394357 http://dx.doi.org/10.1038/oncsis.2017.12 |
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