FTY720 stimulated ROS generation and the Sty1/Atf1 signaling pathway in the fission yeast Schizosaccharomyces pombe

Kanako Hagihara, Aya Mizukura, Yuki Kitai, Mariko Yao, Kouki Ishida, Ayako Kita, Tatsuki Kunoh, Takashi Masuko, Sumio Matzno, Kenji Chiba, Reiko Sugiura

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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.

Original languageEnglish
Pages (from-to)325-337
Number of pages13
JournalGenes to Cells
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 2014

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ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Hagihara, K., Mizukura, A., Kitai, Y., Yao, M., Ishida, K., Kita, A., Kunoh, T., Masuko, T., Matzno, S., Chiba, K., & Sugiura, R. (2014). FTY720 stimulated ROS generation and the Sty1/Atf1 signaling pathway in the fission yeast Schizosaccharomyces pombe. Genes to Cells, 19(4), 325-337. https://doi.org/10.1111/gtc.12134