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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...

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Autores principales: Sohn, Dennis, Peters, Dominik, Piekorz, Roland P., Budach, Wilfried, Jänicke, Reiner U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
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.
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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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