Cargando…

Stretching magnitude–dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis

Previously, we had shown that high magnitude stretch (HMS), rather than low magnitude stretch (LMS), induced significant apoptosis of skeletal muscle C2C12 myoblasts. However, the molecular mechanism remains obscure. In this study, we found that p53 protein accumulated in the nucleus of LMS-loaded c...

Descripción completa

Detalles Bibliográficos
Autores principales: Song, Jing, Wang, Yaqi, Yuan, Xiao, Ji, Qiuxia, Fan, Cunhui, Zhao, Hongmei, Hao, Wenjing, Ren, Dapeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724521/
https://www.ncbi.nlm.nih.gov/pubmed/30865562
http://dx.doi.org/10.1091/mbc.E18-12-0770
_version_ 1783449012898103296
author Song, Jing
Wang, Yaqi
Yuan, Xiao
Ji, Qiuxia
Fan, Cunhui
Zhao, Hongmei
Hao, Wenjing
Ren, Dapeng
author_facet Song, Jing
Wang, Yaqi
Yuan, Xiao
Ji, Qiuxia
Fan, Cunhui
Zhao, Hongmei
Hao, Wenjing
Ren, Dapeng
author_sort Song, Jing
collection PubMed
description Previously, we had shown that high magnitude stretch (HMS), rather than low magnitude stretch (LMS), induced significant apoptosis of skeletal muscle C2C12 myoblasts. However, the molecular mechanism remains obscure. In this study, we found that p53 protein accumulated in the nucleus of LMS-loaded cells, whereas it translocated into mitochondria of HMS-loaded cells. Knocking down endogenous p53 by shRNA abrogated HMS-induced apoptosis. Furthermore, we demonstrated that overaccumulation of reactive oxygen species (ROS) during HMS-inactivated AKT that was activated in LMS-treated cells, which accounted for the distinct p53 subcellular localizations under HMS and LMS. Blocking ROS generation by N-acetylcysteine (NAC) or overexpressing constitutively active AKT vector (CA-AKT) inhibited HMS-incurred p53 mitochondrial translocation and promoted its nuclear targeting. Moreover, both NAC and CA-AKT significantly attenuated HMS-induced C2C12 apoptosis. Finally, we found that Ser389 phosphorylation of p53 was a downstream event of ROS-inactivated AKT pathway, which was critical to p53 mitochondrial trafficking during HMS stimuli. Transfecting p53-shRNA C2C12s with the mutant p53 (S389A) that was unable to target p53 to mitochondria underwent significantly lower apoptosis than transfection with wild-type p53. Altogether, our study uncovered that mitochondrial localization of p53, resulting from p53 Ser389 phosphorylation through ROS-inactivated AKT pathway, prompted C2C12 myoblast apoptosis during HMS stimulation.
format Online
Article
Text
id pubmed-6724521
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-67245212019-09-05 Stretching magnitude–dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis Song, Jing Wang, Yaqi Yuan, Xiao Ji, Qiuxia Fan, Cunhui Zhao, Hongmei Hao, Wenjing Ren, Dapeng Mol Biol Cell Articles Previously, we had shown that high magnitude stretch (HMS), rather than low magnitude stretch (LMS), induced significant apoptosis of skeletal muscle C2C12 myoblasts. However, the molecular mechanism remains obscure. In this study, we found that p53 protein accumulated in the nucleus of LMS-loaded cells, whereas it translocated into mitochondria of HMS-loaded cells. Knocking down endogenous p53 by shRNA abrogated HMS-induced apoptosis. Furthermore, we demonstrated that overaccumulation of reactive oxygen species (ROS) during HMS-inactivated AKT that was activated in LMS-treated cells, which accounted for the distinct p53 subcellular localizations under HMS and LMS. Blocking ROS generation by N-acetylcysteine (NAC) or overexpressing constitutively active AKT vector (CA-AKT) inhibited HMS-incurred p53 mitochondrial translocation and promoted its nuclear targeting. Moreover, both NAC and CA-AKT significantly attenuated HMS-induced C2C12 apoptosis. Finally, we found that Ser389 phosphorylation of p53 was a downstream event of ROS-inactivated AKT pathway, which was critical to p53 mitochondrial trafficking during HMS stimuli. Transfecting p53-shRNA C2C12s with the mutant p53 (S389A) that was unable to target p53 to mitochondria underwent significantly lower apoptosis than transfection with wild-type p53. Altogether, our study uncovered that mitochondrial localization of p53, resulting from p53 Ser389 phosphorylation through ROS-inactivated AKT pathway, prompted C2C12 myoblast apoptosis during HMS stimulation. The American Society for Cell Biology 2019-05-01 /pmc/articles/PMC6724521/ /pubmed/30865562 http://dx.doi.org/10.1091/mbc.E18-12-0770 Text en © 2019 Song, Wang, et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Song, Jing
Wang, Yaqi
Yuan, Xiao
Ji, Qiuxia
Fan, Cunhui
Zhao, Hongmei
Hao, Wenjing
Ren, Dapeng
Stretching magnitude–dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis
title Stretching magnitude–dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis
title_full Stretching magnitude–dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis
title_fullStr Stretching magnitude–dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis
title_full_unstemmed Stretching magnitude–dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis
title_short Stretching magnitude–dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis
title_sort stretching magnitude–dependent inactivation of akt by ros led to enhanced p53 mitochondrial translocation and myoblast apoptosis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724521/
https://www.ncbi.nlm.nih.gov/pubmed/30865562
http://dx.doi.org/10.1091/mbc.E18-12-0770
work_keys_str_mv AT songjing stretchingmagnitudedependentinactivationofaktbyrosledtoenhancedp53mitochondrialtranslocationandmyoblastapoptosis
AT wangyaqi stretchingmagnitudedependentinactivationofaktbyrosledtoenhancedp53mitochondrialtranslocationandmyoblastapoptosis
AT yuanxiao stretchingmagnitudedependentinactivationofaktbyrosledtoenhancedp53mitochondrialtranslocationandmyoblastapoptosis
AT jiqiuxia stretchingmagnitudedependentinactivationofaktbyrosledtoenhancedp53mitochondrialtranslocationandmyoblastapoptosis
AT fancunhui stretchingmagnitudedependentinactivationofaktbyrosledtoenhancedp53mitochondrialtranslocationandmyoblastapoptosis
AT zhaohongmei stretchingmagnitudedependentinactivationofaktbyrosledtoenhancedp53mitochondrialtranslocationandmyoblastapoptosis
AT haowenjing stretchingmagnitudedependentinactivationofaktbyrosledtoenhancedp53mitochondrialtranslocationandmyoblastapoptosis
AT rendapeng stretchingmagnitudedependentinactivationofaktbyrosledtoenhancedp53mitochondrialtranslocationandmyoblastapoptosis