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ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis
Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and pro...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737032/ https://www.ncbi.nlm.nih.gov/pubmed/31506423 http://dx.doi.org/10.1038/s41419-019-1919-0 |
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author | Zhou, Lei Tan, Jie-hui Cao, Rong-chang Xu, Jia Chen, Xue-mei Qi, Zhao-chang Zhou, Su-ying Li, Su-bing Mo, Qi-xin Li, Zhi-wei Zhang, Guo-wei |
author_facet | Zhou, Lei Tan, Jie-hui Cao, Rong-chang Xu, Jia Chen, Xue-mei Qi, Zhao-chang Zhou, Su-ying Li, Su-bing Mo, Qi-xin Li, Zhi-wei Zhang, Guo-wei |
author_sort | Zhou, Lei |
collection | PubMed |
description | Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1β, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP. |
format | Online Article Text |
id | pubmed-6737032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67370322019-09-11 ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis Zhou, Lei Tan, Jie-hui Cao, Rong-chang Xu, Jia Chen, Xue-mei Qi, Zhao-chang Zhou, Su-ying Li, Su-bing Mo, Qi-xin Li, Zhi-wei Zhang, Guo-wei Cell Death Dis Article Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1β, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP. Nature Publishing Group UK 2019-09-10 /pmc/articles/PMC6737032/ /pubmed/31506423 http://dx.doi.org/10.1038/s41419-019-1919-0 Text en © The Author(s) 2019 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 Zhou, Lei Tan, Jie-hui Cao, Rong-chang Xu, Jia Chen, Xue-mei Qi, Zhao-chang Zhou, Su-ying Li, Su-bing Mo, Qi-xin Li, Zhi-wei Zhang, Guo-wei ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis |
title | ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis |
title_full | ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis |
title_fullStr | ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis |
title_full_unstemmed | ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis |
title_short | ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis |
title_sort | atf6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737032/ https://www.ncbi.nlm.nih.gov/pubmed/31506423 http://dx.doi.org/10.1038/s41419-019-1919-0 |
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