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PEPD is a pivotal regulator of p53 tumor suppressor

p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regress...

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Detalles Bibliográficos
Autores principales: Yang, Lu, Li, Yun, Bhattacharya, Arup, Zhang, Yuesheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727116/
https://www.ncbi.nlm.nih.gov/pubmed/29233996
http://dx.doi.org/10.1038/s41467-017-02097-9
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author Yang, Lu
Li, Yun
Bhattacharya, Arup
Zhang, Yuesheng
author_facet Yang, Lu
Li, Yun
Bhattacharya, Arup
Zhang, Yuesheng
author_sort Yang, Lu
collection PubMed
description p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin and H(2)O(2) each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for the stress response, but this also renders cells dependent on PEPD for survival, as it suppresses p53. This finding provides further understanding of p53 regulation and may have significant implications for the treatment of cancer and other diseases.
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spelling pubmed-57271162017-12-14 PEPD is a pivotal regulator of p53 tumor suppressor Yang, Lu Li, Yun Bhattacharya, Arup Zhang, Yuesheng Nat Commun Article p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin and H(2)O(2) each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for the stress response, but this also renders cells dependent on PEPD for survival, as it suppresses p53. This finding provides further understanding of p53 regulation and may have significant implications for the treatment of cancer and other diseases. Nature Publishing Group UK 2017-12-12 /pmc/articles/PMC5727116/ /pubmed/29233996 http://dx.doi.org/10.1038/s41467-017-02097-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Yang, Lu
Li, Yun
Bhattacharya, Arup
Zhang, Yuesheng
PEPD is a pivotal regulator of p53 tumor suppressor
title PEPD is a pivotal regulator of p53 tumor suppressor
title_full PEPD is a pivotal regulator of p53 tumor suppressor
title_fullStr PEPD is a pivotal regulator of p53 tumor suppressor
title_full_unstemmed PEPD is a pivotal regulator of p53 tumor suppressor
title_short PEPD is a pivotal regulator of p53 tumor suppressor
title_sort pepd is a pivotal regulator of p53 tumor suppressor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727116/
https://www.ncbi.nlm.nih.gov/pubmed/29233996
http://dx.doi.org/10.1038/s41467-017-02097-9
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