title: Oxidative stress-inducible truncated serine/arginine-rich splicing factor 3 regulates interleukin-8 production in human colon cancer cells.
abstract: Serine/arginine-rich splicing factor 3 (SRSF3) is a member of the SR protein family and plays wide-ranging roles in gene expression. The human SRSF3 gene generates two alternative splice transcripts, a major mRNA isoform (SRSF3-FL) encoding functional full-length protein and a premature termination codon (PTC)-containing isoform (SRSF3-PTC). The latter is degraded through nonsense-mediated mRNA decay (NMD). Treatment of a human colon cancer cell line (HCT116) with 100 μM sodium arsenite increased SRSF3-PTC mRNA levels without changing SRSF3-FL mRNA levels. A chemiluminescence-based NMD reporter assay system demonstrated that arsenite treatment inhibited NMD activity and increased SRSF3-PTC mRNA levels in the cytoplasm, facilitating translation of a truncated SRSF3 protein (SRSF3-TR) from SRSF3-PTC mRNA. SRSF3-TR lacked two-thirds of the Arg/Ser-rich (RS) domain whose phosphorylation state is known to be crucial for subcellular distribution. SRSF3-FL was localized in the nucleus, while overexpressed SRSF3-TR was diffusely distributed in the cytoplasm and the nucleus. A part of SRSF3-TR was also associated with stress granules in the cytoplasm. Interestingly, treatment of HCT116 cells with a small interference RNA specifically targeting SRSF3-PTC mRNA significantly attenuated arsenite-stimulated induction of c-JUN protein, its binding activity to the AP-1 binding site (-126 to 120 bp) in the interleukin (IL)-8 gene promoter, and AP-1 promoter activity, resulting in significant reduction of arsenite-stimulated IL-8 production. Our results suggest that SRSF3-TR may function as a positive regulator of oxidative stress-initiated inflammatory responses in colon cancer cells.
authors.affiliation: Department of Stress Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Kano
authors.forename: Kensei
authors.initials: K
authors.lastname: Nishida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kurebe
authors.forename: Chihiro
authors.initials: C
authors.lastname: Nishiyama
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kita
authors.forename: Yoko
authors.initials: Y
authors.lastname: Akaike
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kajita
authors.forename: Ken
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Masuda
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuwano
authors.forename: Toshihito
authors.initials: T
authors.lastname: Tanahashi
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Rokutan
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D018053:Arsenites; D001665:Binding Sites; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D059365:Nonsense Mediated mRNA Decay / Q000187:drug effects; D018384:Oxidative Stress / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D017670:Sodium Compounds; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D018053:Arsenites; D018389:Codon, Nonsense; D016209:Interleukin-8; D020033:Protein Isoforms; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; D017670:Sodium Compounds; D018808:Transcription Factor AP-1; D000068103:Serine-Arginine Splicing Factors; C017947:sodium arsenite
keywords: IL-8; SRSF3 gene; alternative splicing; nonsense-mediated mRNA decay; oxidative stress