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miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21(WAF1/CIP1) and caspase-3
MicroRNAs (miRNAs), a class of small non-coding RNAs that usually cause gene silencing by translational repression or degradation of mRNAs, are implicated in DNA damage-induced stress responses. To identify senescence-associated miRNAs, we performed microarray analyses using wild-type and p53-defici...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941286/ https://www.ncbi.nlm.nih.gov/pubmed/26895377 http://dx.doi.org/10.18632/oncotarget.7432 |
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author | Sohn, Dennis Peters, Dominik Piekorz, Roland P. Budach, Wilfried Jänicke, Reiner U. |
author_facet | Sohn, Dennis Peters, Dominik Piekorz, Roland P. Budach, Wilfried Jänicke, Reiner U. |
author_sort | Sohn, Dennis |
collection | PubMed |
description | MicroRNAs (miRNAs), a class of small non-coding RNAs that usually cause gene silencing by translational repression or degradation of mRNAs, are implicated in DNA damage-induced stress responses. To identify senescence-associated miRNAs, we performed microarray analyses using wild-type and p53-deficient HCT116 colon carcinoma cells that following gamma-irradiation (γIR) are driven into senescence and apoptosis, respectively. Several miRNAs including miR-30e were found upregulated in a p53-dependent manner specifically in senescent cells, but not in apoptotic cells. Overexpression of miR-30e in HCT116 cells not only inhibited γIR-, etoposide- or miR-34a-induced caspase-3-like DEVDase activities and cell death, but greatly accelerated and augmented their senescent phenotype. Consistently, procaspase-3 protein, but not mRNA decreased in the presence of miR-30e, whereas expression of the cyclin-dependent kinase inhibitor p21 increased both at the mRNA and protein level. Performing luciferase reporter gene assays, we identified the 3′-UTR of the caspase-3 mRNA as a direct miR-30e target. In contrast, although miR-30e was unable to bind to the p21 mRNA, it increased expression of a luciferase construct containing the p21 promoter, suggesting that the miR-30e-mediated upregulation of p21 occurs indirectly at the transcriptional level. Interestingly, despite suppressing procaspase-3 expression, miR-30e was unable to protect RKO colon carcinoma cells from DNA damage-induced death or to induce senescence, as miR-30e completely fails to upregulate p21 in these cells. These data suggest that miR-30e functions in a cell type-dependent manner as an important molecular switch for DNA damage-induced stress responses and may thus represent a target of therapeutic value. |
format | Online Article Text |
id | pubmed-4941286 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-49412862016-07-19 miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21(WAF1/CIP1) and caspase-3 Sohn, Dennis Peters, Dominik Piekorz, Roland P. Budach, Wilfried Jänicke, Reiner U. Oncotarget Research Paper MicroRNAs (miRNAs), a class of small non-coding RNAs that usually cause gene silencing by translational repression or degradation of mRNAs, are implicated in DNA damage-induced stress responses. To identify senescence-associated miRNAs, we performed microarray analyses using wild-type and p53-deficient HCT116 colon carcinoma cells that following gamma-irradiation (γIR) are driven into senescence and apoptosis, respectively. Several miRNAs including miR-30e were found upregulated in a p53-dependent manner specifically in senescent cells, but not in apoptotic cells. Overexpression of miR-30e in HCT116 cells not only inhibited γIR-, etoposide- or miR-34a-induced caspase-3-like DEVDase activities and cell death, but greatly accelerated and augmented their senescent phenotype. Consistently, procaspase-3 protein, but not mRNA decreased in the presence of miR-30e, whereas expression of the cyclin-dependent kinase inhibitor p21 increased both at the mRNA and protein level. Performing luciferase reporter gene assays, we identified the 3′-UTR of the caspase-3 mRNA as a direct miR-30e target. In contrast, although miR-30e was unable to bind to the p21 mRNA, it increased expression of a luciferase construct containing the p21 promoter, suggesting that the miR-30e-mediated upregulation of p21 occurs indirectly at the transcriptional level. Interestingly, despite suppressing procaspase-3 expression, miR-30e was unable to protect RKO colon carcinoma cells from DNA damage-induced death or to induce senescence, as miR-30e completely fails to upregulate p21 in these cells. These data suggest that miR-30e functions in a cell type-dependent manner as an important molecular switch for DNA damage-induced stress responses and may thus represent a target of therapeutic value. Impact Journals LLC 2016-02-17 /pmc/articles/PMC4941286/ /pubmed/26895377 http://dx.doi.org/10.18632/oncotarget.7432 Text en Copyright: © 2016 Sohn et al. http://creativecommons.org/licenses/by/2.5/ 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 credited. |
spellingShingle | Research Paper Sohn, Dennis Peters, Dominik Piekorz, Roland P. Budach, Wilfried Jänicke, Reiner U. miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21(WAF1/CIP1) and caspase-3 |
title | miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21(WAF1/CIP1) and caspase-3 |
title_full | miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21(WAF1/CIP1) and caspase-3 |
title_fullStr | miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21(WAF1/CIP1) and caspase-3 |
title_full_unstemmed | miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21(WAF1/CIP1) and caspase-3 |
title_short | miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21(WAF1/CIP1) and caspase-3 |
title_sort | mir-30e controls dna damage-induced stress responses by modulating expression of the cdk inhibitor p21(waf1/cip1) and caspase-3 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941286/ https://www.ncbi.nlm.nih.gov/pubmed/26895377 http://dx.doi.org/10.18632/oncotarget.7432 |
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