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Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts
BACKGROUND: Recent studies have demonstrated that activation of autophagy increases the lifespan of organisms from yeast to flies. In contrast to the lifespan extension effect in lower organisms, it has been reported that overexpression of unc-51-like kinase 3 (ULK3), the mammalian homolog of autoph...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152578/ https://www.ncbi.nlm.nih.gov/pubmed/21858089 http://dx.doi.org/10.1371/journal.pone.0023367 |
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author | Kang, Hyun Tae Lee, Ki Baek Kim, Sung Young Choi, Hae Ri Park, Sang Chul |
author_facet | Kang, Hyun Tae Lee, Ki Baek Kim, Sung Young Choi, Hae Ri Park, Sang Chul |
author_sort | Kang, Hyun Tae |
collection | PubMed |
description | BACKGROUND: Recent studies have demonstrated that activation of autophagy increases the lifespan of organisms from yeast to flies. In contrast to the lifespan extension effect in lower organisms, it has been reported that overexpression of unc-51-like kinase 3 (ULK3), the mammalian homolog of autophagy-specific gene 1 (ATG1), induces premature senescence in human fibroblasts. Therefore, we assessed whether the activation of autophagy would genuinely induce premature senescence in human cells. METHODOLOGY/PRINCIPAL FINDINGS: Depletion of ATG7, ATG12, or lysosomal-associated membrane protein 2 (Lamp2) by transfecting siRNA or infecting cells with a virus containing gene-specific shRNA resulted in a senescence-like state in two strains of primary human fibroblasts. Prematurely senescent cells induced by autophagy impairment exhibited the senescent phenotypes, similar to the replicatively senescent cells, such as increased senescence associated β-galactosidase (SA-β-gal) activity, reactive oxygen species (ROS) generation, and accumulation of lipofuscin. In addition, expression levels of ribosomal protein S6 kinase1 (S6K1), p-S6K1, p-S6, and eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) in the mammalian target of rapamycin (mTOR) pathway and beclin-1, ATG7, ATG12-ATG5 conjugate, and the sequestosome 1 (SQSTM1/p62) monomer in the autophagy pathway were decreased in both the replicatively and the autophagy impairment-induced prematurely senescent cells. Furthermore, it was found that ROS scavenging by N-acetylcysteine (NAC) and inhibition of p53 activation by pifithrin-α or knockdown of p53 using siRNA, respectively, delayed autophagy impairment-induced premature senescence and restored the expression levels of components in the mTOR and autophagy pathways. CONCLUSION: Taken together, we concluded that autophagy impairment induces premature senescence through a ROS- and p53-dependent manner in primary human fibroblasts. |
format | Online Article Text |
id | pubmed-3152578 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31525782011-08-19 Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts Kang, Hyun Tae Lee, Ki Baek Kim, Sung Young Choi, Hae Ri Park, Sang Chul PLoS One Research Article BACKGROUND: Recent studies have demonstrated that activation of autophagy increases the lifespan of organisms from yeast to flies. In contrast to the lifespan extension effect in lower organisms, it has been reported that overexpression of unc-51-like kinase 3 (ULK3), the mammalian homolog of autophagy-specific gene 1 (ATG1), induces premature senescence in human fibroblasts. Therefore, we assessed whether the activation of autophagy would genuinely induce premature senescence in human cells. METHODOLOGY/PRINCIPAL FINDINGS: Depletion of ATG7, ATG12, or lysosomal-associated membrane protein 2 (Lamp2) by transfecting siRNA or infecting cells with a virus containing gene-specific shRNA resulted in a senescence-like state in two strains of primary human fibroblasts. Prematurely senescent cells induced by autophagy impairment exhibited the senescent phenotypes, similar to the replicatively senescent cells, such as increased senescence associated β-galactosidase (SA-β-gal) activity, reactive oxygen species (ROS) generation, and accumulation of lipofuscin. In addition, expression levels of ribosomal protein S6 kinase1 (S6K1), p-S6K1, p-S6, and eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) in the mammalian target of rapamycin (mTOR) pathway and beclin-1, ATG7, ATG12-ATG5 conjugate, and the sequestosome 1 (SQSTM1/p62) monomer in the autophagy pathway were decreased in both the replicatively and the autophagy impairment-induced prematurely senescent cells. Furthermore, it was found that ROS scavenging by N-acetylcysteine (NAC) and inhibition of p53 activation by pifithrin-α or knockdown of p53 using siRNA, respectively, delayed autophagy impairment-induced premature senescence and restored the expression levels of components in the mTOR and autophagy pathways. CONCLUSION: Taken together, we concluded that autophagy impairment induces premature senescence through a ROS- and p53-dependent manner in primary human fibroblasts. Public Library of Science 2011-08-08 /pmc/articles/PMC3152578/ /pubmed/21858089 http://dx.doi.org/10.1371/journal.pone.0023367 Text en Kang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kang, Hyun Tae Lee, Ki Baek Kim, Sung Young Choi, Hae Ri Park, Sang Chul Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts |
title | Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts |
title_full | Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts |
title_fullStr | Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts |
title_full_unstemmed | Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts |
title_short | Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts |
title_sort | autophagy impairment induces premature senescence in primary human fibroblasts |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152578/ https://www.ncbi.nlm.nih.gov/pubmed/21858089 http://dx.doi.org/10.1371/journal.pone.0023367 |
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