title: miR-15b/16-2 regulates factors that promote p53 phosphorylation and augments the DNA damage response following radiation in the lung.
abstract: MicroRNAs (miRNAs) are regulatory RNAs frequently dysregulated in disease and following cellular stress. Investigators have described changes in miR-15b expression following exposure to several stress-inducing anticancer agents, including ionizing radiation (IR), etoposide, and hydrogen peroxide. However, the role for miR-15b as a mediator of cellular injury in organs such as the lung has yet to be explored. In this study, we examined miR-15b expression patterns as well as its potential role in DNA damage and repair in the setting of IR exposure. We showed that miR-15b is up-regulated in a dose- and time-dependent manner in human bronchial epithelial cells following IR. miR-15b expression was highest after 2 h of IR and decreased gradually. Survival rates following IR were also higher in miR-15b/16-2-overexpressing cells. Cell cycle arrest in G2/M phase and an increased DNA repair response were observed in IR-exposed miR-15b/16-2 stable cells. We observed an up-regulation of components of the ataxia telangiectasia mutated (ATM)/Chek1/p53 pathway in miR-15b/16-2-overexpressing cells after IR. Moreover, a pathway-based PCR expression array of genes demonstrated that miR-15b/16-2 overexpression significantly induced the expression of genes involved in ATM/ataxia telangiectasia and Rad-3-related (ATR) signaling, apoptosis, the cell cycle, and DNA repair pathways. Here we demonstrated a novel biological link between miR-15b and DNA damage and cellular protection in lung cells. We identified Wip1 (PPM1D) as a functional target for miR-15b and determined that miR-15b induction of the DNA damage response is partially dependent upon suppression of Wip1. Our study suggests that miR-15b/Wip1 could be a potential therapeutic target in radiation-induced lung disease.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Rahman
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Giulia
authors.initials: G
authors.lastname: Romano
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Federica
authors.initials: F
authors.lastname: Calore
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Mario
authors.initials: M
authors.lastname: Acunzo
authors.affiliation: Department of Radiation Oncology, and The Ohio State University, Columbus, Ohio 43210; James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210.
authors.forename: Erica Hlavin
authors.initials: EH
authors.lastname: Bell
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio 43210; James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210. Electronic address: patrick.nana-sinkam@osumc.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nana-Sinkam
mesh_terms: D020413:3' Untranslated Regions; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D004847:Epithelial Cells / Q000502:physiology* / Q000528:radiation effects; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D008168:Lung / Q000473:pathology; D035683:MicroRNAs / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D020545:Respiratory Mucosa / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: Apoptosis; Cell Cycle; Cell Signaling; DNA Damage Response; DNA Repair; Gene Knockout; Irradiation; miR-15b; miR-16-2; p53 Phosphorylation
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