title: Alternative Splicing of STAT3 Is Affected by RNA Editing.
abstract: A-to-I RNA editing, carried out by adenosine deaminase acting on RNA (ADAR) enzymes, is an epigenetic phenomenon of posttranscriptional modifications on pre-mRNA. RNA editing in intronic sequences may influence alternative splicing of flanking exons. We have previously shown that conditions that induce editing result in elevated expression of signal transducer and activator of transcription 3 (STAT3), preferentially the alternatively-spliced STAT3β isoform. Mechanisms regulating alternative splicing of STAT3 have not been elucidated. STAT3 undergoes A-to-I RNA editing in an intron residing in proximity to the alternatively spliced exon. We hypothesized that RNA editing plays a role in regulating alternative splicing toward STAT3β. In this study we extend our observation connecting RNA editing to the preferential induction of STAT3β expression. We study the involvement of ADAR1 in STAT3 editing and reveal the connection between editing and alternative splicing of STAT3. Deferoaxamine treatment caused the induction in STAT3 RNA editing and STAT3β expression. Silencing ADAR1 caused a decrease in STAT3 editing and expression with a preferential decrease in STAT3β. Cells transfected with a mutated minigene showed preferential splicing toward the STAT3β transcript. Editing in the STAT3 intron is performed by ADAR1 and affects STAT3 alternative splicing. These results suggest that RNA editing is one of the molecular mechanisms regulating the expression of STAT3β.
authors.affiliation: 1 Department of Pediatric Critical Care Medicine, Safra Children's Hospital, Sheba Medical Center , Tel Hashomer, Israel .|2 Sackler Medical School, Tel-Aviv University , Tel-Aviv, Israel .
authors.forename: Lior
authors.initials: L
authors.lastname: Goldberg
authors.affiliation: 1 Department of Pediatric Critical Care Medicine, Safra Children's Hospital, Sheba Medical Center , Tel Hashomer, Israel .|2 Sackler Medical School, Tel-Aviv University , Tel-Aviv, Israel .
authors.forename: Mor
authors.initials: M
authors.lastname: Abutbul-Amitai
authors.affiliation: 1 Department of Pediatric Critical Care Medicine, Safra Children's Hospital, Sheba Medical Center , Tel Hashomer, Israel .|2 Sackler Medical School, Tel-Aviv University , Tel-Aviv, Israel .
authors.forename: Gideon
authors.initials: G
authors.lastname: Paret
authors.affiliation: 1 Department of Pediatric Critical Care Medicine, Safra Children's Hospital, Sheba Medical Center , Tel Hashomer, Israel .
authors.forename: Yael
authors.initials: Y
authors.lastname: Nevo-Caspi
mesh_terms: D000243:Adenosine Deaminase / Q000502:physiology*; D017398:Alternative Splicing / Q000235:genetics; D020087:Alu Elements; D001483:Base Sequence; D002461:Cell Line, Transformed; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D017393:RNA Editing / Q000502:physiology*; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000595356:ADAR protein, human; D000243:Adenosine Deaminase
keywords: A-to-I RNA editing; ADAR enzyme; Alu elements; STAT3; alternative splicing