title: Activation of protein phosphatase causes alternative splicing of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL): potential effect on immune surveillance.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the TNF superfamily of proteins. It is highly expressed on natural killer cells, cytotoxic T lymphocytes, and monocytes after stimulation, and plays a critical role in immune surveillance. Two splice variants of TRAIL were identified recently that show no proapoptotic activity. Phosphorylation level in splicing factors, serine-arginine-rich (SR) and heterogeneous ribonucleoproteins (hnRNPs) govern the mRNA splicing of several apoptosis-related genes. We characterized the apoptotic stimuli-mediated alternative splicing pattern of TRAIL and investigated the possible underlying mechanism of alternative splicing. Etoposide and cycloheximide induced alternative splicing, whereas staurosporine (a broad kinase inhibitor) blocked both constitutive and alternative splicing. De novo ceramide synthesis and subsequent protein phosphatase-1 (PP-1) activation enhanced the alternative splicing, as did TNF-alpha but not interferon alpha (IFN-alpha) stimulation. We demonstrated that TRAIL alters gene expression through mRNA splicing and may change proapoptotic potential in response to cytokine stimulation.
authors.affiliation: Department of Internal Medicine, Unit of Translational Medicine, Graduate School of Biomedical Science, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. kamachi-ngs@umin.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamachi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Aramaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Tanimura
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ichinose
authors.forename: Keita
authors.initials: K
authors.lastname: Fujikawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Iwamoto
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yoshizaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kohno
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D017398:Alternative Splicing / Q000235:genetics* / Q000276:immunology; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000276:immunology; D054645:Protein Phosphatase 1; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000276:immunology; D020298:U937 Cells
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1