title: Regulation of miR-155 biogenesis in cystic fibrosis lung epithelial cells: antagonistic role of two mRNA-destabilizing proteins, KSRP and TTP.
abstract: Cystic fibrosis (CF) is characterized by a massive pro-inflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyper-expression of IL-8 protein through elevated expression of miR-155. We therefore investigated what factors promote the enhanced aberrant expression of miR-155 in CF. Here we report for the first time, the role of mRNA-destabilizing inflammatory RNA-binding proteins, KSRP and TTP, in the regulation of miR-155 biogenesis in CF lung epithelial cells. We find that KSRP and TTP have an antagonistic role in miR-155 biogenesis. While KSRP promotes enhanced processing of miR-155 precursors to mature miR-155, over-expression of TTP in the CF lung epithelial cells suppresses expression of miR-155. We find that TTP induces the expression of miR-1, which appears to be a regulator of miR-155 biogenesis in CF lung epithelial cells. These data provide novel insights into the mechanisms that induce hyper-inflammatory phenotype of CF, and are potential candidates for anti-inflammatory therapeutics for CF.
authors.affiliation: Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Parameet
authors.initials: P
authors.lastname: Kumar
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Anirban
authors.initials: A
authors.lastname: Bhattacharyya
authors.forename: Roopa
authors.initials: R
authors.lastname: Biswas
mesh_terms: D045744:Cell Line, Tumor; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*
chemical_list: C105789:KHSRP protein, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D051816:Tristetraprolin; C497552:ZFP36 protein, human