title: FTY720 stimulated ROS generation and the Sty1/Atf1 signaling pathway in the fission yeast Schizosaccharomyces pombe.
abstract: Fingolimod hydrochloride (FTY720) is the first-in-class immune modulator known as sphingosine 1-phosphate (S1P) receptor agonists. FTY720 has also been reported to exert a variety of physiological functions such as antitumor effect, angiogenesis inhibition, and Ca2+ mobilization. Here, we show that FTY720 treatment induced reactive oxygen species (ROS) accumulation, and investigated the effect of FTY720 on the stress-activated MAP kinase Spc1/Sty1, a functional homologue of p38 MAPK, using a Renilla luciferase reporter construct fused to the CRE, which gives an accurate measure of the transcriptional activity of Atf1 and thus serves as a faithful readout of the Spc1/Sty1 MAPK signaling in response to oxidative stresses. FTY720 stimulated the CRE responses in a concentration-dependent manner, which was markedly reduced by deletion of the components of the Spc1/Sty1 MAPK pathway. The blockade of ROS production by NAC (N-acetyl-L-cysteine) significantly reversed the FTY720-induced ROS accumulation, subsequent activation of the Spc1/Sty1 MAPK pathway, and inhibition of cell proliferation. Cells lacking the components of the Spc1/Sty1 MAPK exhibited higher sensitivity to FTY720 and higher ROS levels upon FTY720 treatment than in wild-type cells. Thus, our results demonstrate the usefulness of fission yeast for elucidating the FTY720-mediated signaling pathways involving ROS.
authors: Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan; Japan Society for the Promotion of Science, 1-8 Chiyoda-ku, Tokyo, 102-8472, Japan.
authors: Kanako
authors: K
authors: Hagihara
authors: Aya
authors: A
authors: Mizukura
authors: Yuki
authors: Y
authors: Kitai
authors: Mariko
authors: M
authors: Yao
authors: Kouki
authors: K
authors: Ishida
authors: Ayako
authors: A
authors: Kita
authors: Tatsuki
authors: T
authors: Kunoh
authors: Takashi
authors: T
authors: Masuko
authors: Sumio
authors: S
authors: Matzno
authors: Kenji
authors: K
authors: Chiba
authors: Reiko
authors: R
authors: Sugiura
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D051697:Activating Transcription Factor 1 / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D000068876:Fingolimod Hydrochloride; D016166:Free Radical Scavengers / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011409:Propylene Glycols / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D051697:Activating Transcription Factor 1; D016166:Free Radical Scavengers; D007166:Immunosuppressive Agents; D010750:Phosphoproteins; D011409:Propylene Glycols; D017382:Reactive Oxygen Species; D029702:Schizosaccharomyces pombe Proteins; C106740:atf1 protein, S pombe; D020928:Mitogen-Activated Protein Kinases; C095409:sty1 protein, S pombe; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002118:Calcium; D000111:Acetylcysteine