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Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library
Cell cycle progression is a tightly controlled fundamental process in living cells, with any defects being closely linked to various abnormalities. The tumor suppressor p53/p21 axis is a core pathway controlling cell cycle progression; however, its regulatory mechanism has not been fully elucidated....
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647124/ https://www.ncbi.nlm.nih.gov/pubmed/29057323 http://dx.doi.org/10.1126/sciadv.1701383 |
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author | Huang, Can Wu, Shourong Ji, Hong Yan, Xuesong Xie, Yudan Murai, Saomi Zhao, Hezhao Miyagishi, Makoto Kasim, Vivi |
author_facet | Huang, Can Wu, Shourong Ji, Hong Yan, Xuesong Xie, Yudan Murai, Saomi Zhao, Hezhao Miyagishi, Makoto Kasim, Vivi |
author_sort | Huang, Can |
collection | PubMed |
description | Cell cycle progression is a tightly controlled fundamental process in living cells, with any defects being closely linked to various abnormalities. The tumor suppressor p53/p21 axis is a core pathway controlling cell cycle progression; however, its regulatory mechanism has not been fully elucidated. In an effort to unravel this crucial network, we screened a short hairpin RNA expression vector library and identified unspliced X-box binding protein 1 (XBP1-u) as a novel and critical regulator of the p53/p21 axis. Specifically, XBP1-u negatively regulates the p53/p21 axis by enhancing p53 ubiquitination, which in turn down-regulates p21 expression. We show that XBP1-u suppression induces G(0)-G(1) phase arrest and represses cell proliferation. We further report that the carboxyl terminus of XBP1-u, which differs from that of its spliced form (XBP1-s) due to a codon shift, binds and stabilizes mouse double minute homolog 2 (MDM2) protein, a negative regulator of p53, by inhibiting its self-ubiquitination. Concomitantly, XBP-u overexpression enhances tumorigenesis by positively regulating MDM2. Together, our findings suggest that XBP1-u functions far beyond being merely a precursor of XBP1-s and, instead, is involved in fundamental biological processes. Furthermore, this study provides new insights regarding the regulation of the MDM2/p53/p21 axis. |
format | Online Article Text |
id | pubmed-5647124 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-56471242017-10-22 Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library Huang, Can Wu, Shourong Ji, Hong Yan, Xuesong Xie, Yudan Murai, Saomi Zhao, Hezhao Miyagishi, Makoto Kasim, Vivi Sci Adv Research Articles Cell cycle progression is a tightly controlled fundamental process in living cells, with any defects being closely linked to various abnormalities. The tumor suppressor p53/p21 axis is a core pathway controlling cell cycle progression; however, its regulatory mechanism has not been fully elucidated. In an effort to unravel this crucial network, we screened a short hairpin RNA expression vector library and identified unspliced X-box binding protein 1 (XBP1-u) as a novel and critical regulator of the p53/p21 axis. Specifically, XBP1-u negatively regulates the p53/p21 axis by enhancing p53 ubiquitination, which in turn down-regulates p21 expression. We show that XBP1-u suppression induces G(0)-G(1) phase arrest and represses cell proliferation. We further report that the carboxyl terminus of XBP1-u, which differs from that of its spliced form (XBP1-s) due to a codon shift, binds and stabilizes mouse double minute homolog 2 (MDM2) protein, a negative regulator of p53, by inhibiting its self-ubiquitination. Concomitantly, XBP-u overexpression enhances tumorigenesis by positively regulating MDM2. Together, our findings suggest that XBP1-u functions far beyond being merely a precursor of XBP1-s and, instead, is involved in fundamental biological processes. Furthermore, this study provides new insights regarding the regulation of the MDM2/p53/p21 axis. American Association for the Advancement of Science 2017-10-18 /pmc/articles/PMC5647124/ /pubmed/29057323 http://dx.doi.org/10.1126/sciadv.1701383 Text en Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Huang, Can Wu, Shourong Ji, Hong Yan, Xuesong Xie, Yudan Murai, Saomi Zhao, Hezhao Miyagishi, Makoto Kasim, Vivi Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library |
title | Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library |
title_full | Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library |
title_fullStr | Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library |
title_full_unstemmed | Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library |
title_short | Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library |
title_sort | identification of xbp1-u as a novel regulator of the mdm2/p53 axis using an shrna library |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647124/ https://www.ncbi.nlm.nih.gov/pubmed/29057323 http://dx.doi.org/10.1126/sciadv.1701383 |
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