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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 - 2014
Externally publishedYes

Fingerprint

Schizosaccharomyces
Reactive Oxygen Species
Renilla Luciferases
Fingolimod Hydrochloride
Lysosphingolipid Receptors
p38 Mitogen-Activated Protein Kinases
Cellular Structures
Cysteine
Oxidative Stress
Phosphotransferases
Cell Proliferation

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Hagihara, K., Mizukura, A., Kitai, Y., Yao, M., Ishida, K., Kita, A., ... 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

FTY720 stimulated ROS generation and the Sty1/Atf1 signaling pathway in the fission yeast Schizosaccharomyces pombe. / Hagihara, Kanako; Mizukura, Aya; Kitai, Yuki; Yao, Mariko; Ishida, Kouki; Kita, Ayako; Kunoh, Tatsuki; Masuko, Takashi; Matzno, Sumio; Chiba, Kenji; Sugiura, Reiko.

In: Genes to Cells, Vol. 19, No. 4, 2014, p. 325-337.

Research output: Contribution to journalArticle

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, vol. 19, no. 4, pp. 325-337. https://doi.org/10.1111/gtc.12134
Hagihara, Kanako ; Mizukura, Aya ; Kitai, Yuki ; Yao, Mariko ; Ishida, Kouki ; Kita, Ayako ; Kunoh, Tatsuki ; Masuko, Takashi ; Matzno, Sumio ; Chiba, Kenji ; Sugiura, Reiko. / FTY720 stimulated ROS generation and the Sty1/Atf1 signaling pathway in the fission yeast Schizosaccharomyces pombe. In: Genes to Cells. 2014 ; Vol. 19, No. 4. pp. 325-337.
@article{e2154d45b95447eeb7fb48053f201879,
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.",
author = "Kanako Hagihara and Aya Mizukura and Yuki Kitai and Mariko Yao and Kouki Ishida and Ayako Kita and Tatsuki Kunoh and Takashi Masuko and Sumio Matzno and Kenji Chiba and Reiko Sugiura",
year = "2014",
doi = "10.1111/gtc.12134",
language = "English",
volume = "19",
pages = "325--337",
journal = "Genes to Cells",
issn = "1356-9597",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - FTY720 stimulated ROS generation and the Sty1/Atf1 signaling pathway in the fission yeast Schizosaccharomyces pombe

AU - Hagihara, Kanako

AU - Mizukura, Aya

AU - Kitai, Yuki

AU - Yao, Mariko

AU - Ishida, Kouki

AU - Kita, Ayako

AU - Kunoh, Tatsuki

AU - Masuko, Takashi

AU - Matzno, Sumio

AU - Chiba, Kenji

AU - Sugiura, Reiko

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84897028089&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897028089&partnerID=8YFLogxK

U2 - 10.1111/gtc.12134

DO - 10.1111/gtc.12134

M3 - Article

VL - 19

SP - 325

EP - 337

JO - Genes to Cells

JF - Genes to Cells

SN - 1356-9597

IS - 4

ER -