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FTY 720 stimulated ROS generation and the S ty1/ A tf1 signaling pathway in the fission yeast S chizosaccharomyces pombe
Author(s) -
Hagihara Kanako,
Mizukura Aya,
Kitai Yuki,
Yao Mariko,
Ishida Kouki,
Kita Ayako,
Kunoh Tatsuki,
Masuko Takashi,
Matzno Sumio,
Chiba Kenji,
Sugiura Reiko
Publication year - 2014
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12134
Subject(s) - mapk/erk pathway , biology , reactive oxygen species , signal transduction , p38 mitogen activated protein kinases , schizosaccharomyces pombe , kinase , microbiology and biotechnology , biochemistry , yeast , saccharomyces cerevisiae
Fingolimod hydrochloride ( FTY 720) is the first‐in‐class immune modulator known as sphingosine 1‐phosphate ( S 1 P ) receptor agonists. FTY 720 has also been reported to exert a variety of physiological functions such as antitumor effect, angiogenesis inhibition, and C a 2+ mobilization. Here, we show that FTY 720 treatment induced reactive oxygen species ( ROS ) accumulation, and investigated the effect of FTY 720 on the stress‐activated MAP kinase S pc1/ S ty1, a functional homologue of p38 MAPK , using a R enilla luciferase reporter construct fused to the CRE , which gives an accurate measure of the transcriptional activity of A tf1 and thus serves as a faithful readout of the S pc1/ S ty1 MAPK signaling in response to oxidative stresses. FTY 720 stimulated the CRE responses in a concentration‐dependent manner, which was markedly reduced by deletion of the components of the S pc1/ S ty1 MAPK pathway. The blockade of ROS production by NAC ( N ‐acetyl‐ l ‐cysteine) significantly reversed the FTY 720‐induced ROS accumulation, subsequent activation of the S pc1/ S ty1 MAPK pathway, and inhibition of cell proliferation. Cells lacking the components of the S pc1/ S ty1 MAPK exhibited higher sensitivity to FTY 720 and higher ROS levels upon FTY 720 treatment than in wild‐type cells. Thus, our results demonstrate the usefulness of fission yeast for elucidating the FTY 720‐mediated signaling pathways involving ROS .