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Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression
Cells exposed to ER-stress undergo the Unfolded Protein Response (UPR) to avoid apoptosis, but may also activate autophagy. However, the signal for selection of one of these two protective responses is unknown. To clarify the key switch between autophagy and apoptosis, we examined the correlation of...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798192/ https://www.ncbi.nlm.nih.gov/pubmed/24167719 http://dx.doi.org/10.1242/bio.20135033 |
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author | Matsumoto, Hiroki Miyazaki, Shuichi Matsuyama, Satoshi Takeda, Masayuki Kawano, Makoto Nakagawa, Hiroshi Nishimura, Kazuhiko Matsuo, Saburo |
author_facet | Matsumoto, Hiroki Miyazaki, Shuichi Matsuyama, Satoshi Takeda, Masayuki Kawano, Makoto Nakagawa, Hiroshi Nishimura, Kazuhiko Matsuo, Saburo |
author_sort | Matsumoto, Hiroki |
collection | PubMed |
description | Cells exposed to ER-stress undergo the Unfolded Protein Response (UPR) to avoid apoptosis, but may also activate autophagy. However, the signal for selection of one of these two protective responses is unknown. To clarify the key switch between autophagy and apoptosis, we examined the correlation of UPR-related signals with autophagy and/or apoptosis inductions in HepG2 cells exposed to three ER-stress inducers (NaF, tunicamycin, and thapsigargin) with time, including the effect of small interfering RNA on the cell responses. Thapsigargin-induced ER-stress caused only apoptosis after ∼2 hr with Ire1 phosphorylation, and Grp78, ATF4, and CHOP expressions. On the other hand, NaF- and tunicamycin-induced ER-stress caused only autophagy in the early stage by ∼8 hr with ATF4 expression and without CHOP expression. ATF4-siRNA completely inhibited the autophagy induced by NaF or tunicamycin with suppressed ATF4 protein and mRNA expressions, and also inhibited apoptosis by thapsigargin with suppression of both ATF4 and CHOP. CHOP-siRNA had no effect on autophagy activation by NaF and tunicamycin. On the other hand, CHOP-siRNA activated autophagy in thapsigargin-induced ER-stress with significant ATF4 expression, and suppressed apoptosis with CHOP suppression. These results showed that ATF4 is the key signal for autophagy induced by ER-stress, and that autophagy is switched to apoptosis by subsequent CHOP upregulation, suggesting that the changeover switch between autophagy and apoptosis is located between ATF4 to CHOP in the PERK pathway. |
format | Online Article Text |
id | pubmed-3798192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Company of Biologists |
record_format | MEDLINE/PubMed |
spelling | pubmed-37981922013-10-28 Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression Matsumoto, Hiroki Miyazaki, Shuichi Matsuyama, Satoshi Takeda, Masayuki Kawano, Makoto Nakagawa, Hiroshi Nishimura, Kazuhiko Matsuo, Saburo Biol Open Research Article Cells exposed to ER-stress undergo the Unfolded Protein Response (UPR) to avoid apoptosis, but may also activate autophagy. However, the signal for selection of one of these two protective responses is unknown. To clarify the key switch between autophagy and apoptosis, we examined the correlation of UPR-related signals with autophagy and/or apoptosis inductions in HepG2 cells exposed to three ER-stress inducers (NaF, tunicamycin, and thapsigargin) with time, including the effect of small interfering RNA on the cell responses. Thapsigargin-induced ER-stress caused only apoptosis after ∼2 hr with Ire1 phosphorylation, and Grp78, ATF4, and CHOP expressions. On the other hand, NaF- and tunicamycin-induced ER-stress caused only autophagy in the early stage by ∼8 hr with ATF4 expression and without CHOP expression. ATF4-siRNA completely inhibited the autophagy induced by NaF or tunicamycin with suppressed ATF4 protein and mRNA expressions, and also inhibited apoptosis by thapsigargin with suppression of both ATF4 and CHOP. CHOP-siRNA had no effect on autophagy activation by NaF and tunicamycin. On the other hand, CHOP-siRNA activated autophagy in thapsigargin-induced ER-stress with significant ATF4 expression, and suppressed apoptosis with CHOP suppression. These results showed that ATF4 is the key signal for autophagy induced by ER-stress, and that autophagy is switched to apoptosis by subsequent CHOP upregulation, suggesting that the changeover switch between autophagy and apoptosis is located between ATF4 to CHOP in the PERK pathway. The Company of Biologists 2013-08-27 /pmc/articles/PMC3798192/ /pubmed/24167719 http://dx.doi.org/10.1242/bio.20135033 Text en © 2013. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Matsumoto, Hiroki Miyazaki, Shuichi Matsuyama, Satoshi Takeda, Masayuki Kawano, Makoto Nakagawa, Hiroshi Nishimura, Kazuhiko Matsuo, Saburo Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression |
title | Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression |
title_full | Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression |
title_fullStr | Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression |
title_full_unstemmed | Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression |
title_short | Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression |
title_sort | selection of autophagy or apoptosis in cells exposed to er-stress depends on atf4 expression pattern with or without chop expression |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798192/ https://www.ncbi.nlm.nih.gov/pubmed/24167719 http://dx.doi.org/10.1242/bio.20135033 |
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