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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2019
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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 |
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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 |
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