Activation of protein phosphatase causes alternative splicing of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL): potential effect on immune surveillance.
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.
Kamachi
Makoto
M
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
Aramaki
Toshiyuki
T
Tanimura
Susumu
S
Ichinose
Kunihiro
K
Fujikawa
Keita
K
Iwamoto
Naoki
N
Yoshizaki
Ayumi
A
Ida
Hiroaki
H
Kawakami
Atsushi
A
Kohno
Michiaki
M
Eguchi
Katsumi
K
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
D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1