title: Splicing inhibition induces gene expression through canonical NF-κB pathway and extracellular signal-related kinase activation.
abstract: Splicing, a process for mRNA maturation, is essential for correct gene expression after transcription. However, recent studies also suggest that splicing affects transcription, but its mechanism remains elusive. We previously reported that treatment with spliceostatin A (SSA), a specific splicing inhibitor targeting the splicing factor SF3b, leads to transcriptional activation of a small subset of genes. To investigate the underlying mechanism we utilized luciferase reporters driven by the Interleukin 8 (IL-8) and cytomegalovirus (CMV) promoters, as both recruit a similar set of transcription factors. We also found that SSA treatment led to increased extracellular signal-regulated protein kinase (ERK) activity and that chemical inhibition of ERK also led to decreased promoter activation. Systematic deletion studies suggested that NF-κB activation is mainly responsible for SSA-induced promoters activation.
authors.affiliation: Chemical Genetic Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, 645 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
authors.forename: Khalid
authors.initials: K
authors.lastname: Khan
authors.affiliation: Chemical Genetic Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: tsp@riken.jp.
authors.forename: Tilman
authors.initials: T
authors.lastname: Schneider-Poetsch
authors.affiliation: Chemical Genetic Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ishfaq
authors.affiliation: Chemical Genetic Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, 645 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.affiliation: Chemical Genetic Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Yoshimoto
authors.affiliation: Cancer Research Institute of Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.affiliation: Chemical Genetic Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, 645 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan. Electronic address: yoshidam@riken.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015870:Gene Expression; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011714:Pyrans / Q000494:pharmacology; D012326:RNA Splicing / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016209:Interleukin-8; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011714:Pyrans; C498143:RELA protein, human; D013141:Spiro Compounds; D051996:Transcription Factor RelA; C553684:spliceostatin A; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Extracellular signal-regulated protein kinase; NF-κB; Spliceostatin A