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- W2315790926 abstract "// Dennis Sohn 1 , Dominik Peters 1 , Roland P. Piekorz 2 , Wilfried Budach 1 , Reiner U. Jänicke 1 1 Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty of the Heinrich-Heine-University, Düsseldorf, Germany 2 Institute for Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine-University, Düsseldorf, Germany Correspondence to: Reiner U. Jänicke, e-mail: janicke@uni-duesseldorf.de Keywords: apoptosis, senescence, microRNA-30e, p21, caspase-3 Received: October 01, 2015 Accepted: February 05, 2016 Published: February 17, 2016 ABSTRACT 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." @default.
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- W2315790926 date "2016-02-17" @default.
- W2315790926 modified "2023-10-18" @default.
- W2315790926 title "miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21WAF1/CIP1 and caspase-3" @default.
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- W2315790926 doi "https://doi.org/10.18632/oncotarget.7432" @default.
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