Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fingolimod hydrochloride (FTY720) is the first in class of sphingosine 1-phosphate (S1P) receptor modulator approved to treat multiple sclerosis via down-regulation of G protein-coupled S1P receptor 1 by its phosphorylated form (FTY720-P). Many studies have revealed that FTY720 exerts various biological effects, including antitumor activities, angiogenesis inhibition, Ca(2+) mobilization and apoptosis, independently of S1P receptors. However, the exact mechanisms underlying their effects or signaling pathways mediated by FTY720 have not been completely established. To gain further insights into molecular mechanisms of FTY720 action, the effect of FTY720 on Ca(2+) signaling in fission yeast was analyzed. The addition of Ca(2+) enhanced the sensitivity induced by FTY720, and mutants lacking genes required for calcium homeostasis, including calcineurin and its downstream transcription factor, Ppb1-responsive zinc finger protein (Prz1), were hypersensitive to FTY720 and CaCl2. The effect of FTY720 on calcineurin signaling was monitored by utilizing a luciferase reporter construct fused to three tandem repeats of the calcineurin-dependent response element (CDRE), which gives an accurate measure of calcineurin activity. The addition of FTY720 increased calcineurin activity as well as Ca(2+) influx in a concentration-dependent manner. Notably, the FTY720-mediated Ca(2+) influx and calcineurin activation were reduced markedly by the deletion of yam8 (+) or cch1 (+) encoding putative subunits of a Ca(2+) channel. Consistently, the deletion of Pmk1 mitogen-activated protein kinase (MAPK), which plays an important role in the activation of the Yam8/Cch1 channel, markedly decreased the intracellular Ca(2+) levels upon FTY720 treatment. These results suggest that the FTY720-stimulated Ca(2+)/calcineurin signaling activation partly involves the Yam8/Cch1 channel in fission yeast.
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PMID:Fingolimod (FTY720) stimulates Ca(2+)/calcineurin signaling in fission yeast. 2431 1

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.
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PMID:FTY720 stimulated ROS generation and the Sty1/Atf1 signaling pathway in the fission yeast Schizosaccharomyces pombe. 2450 81

Fingolimod hydrochloride (FTY720), a sphingosine-1-phosphate (S1P) analogue, is an approved immune modulator for the treatment of multiple sclerosis (MS). Notably, in addition to its well-known mode of action as an S1P modulator, accumulating evidence suggests that FTY720 induces apoptosis in various cancer cells via reactive oxygen species (ROS) generation. Although the involvement of multiple signaling molecules, such as JNK (Jun N-terminal kinase), Akt (alpha serine/threonine-protein kinase) and Sphk has been reported, the exact mechanisms how FTY720 induces cell growth inhibition and the functional relationship between FTY720 and these signaling pathways remain elusive. Our previous reports using the fission yeast Schizosaccharomyces pombe as a model system to elucidate FTY720-mediated signaling pathways revealed that FTY720 induces an increase in intracellular Ca2+ concentrations and ROS generation, which resulted in the activation of the transcriptional responses downstream of Ca2+/calcineurin signaling and stress-activated MAPK signaling, respectively. Here, we performed a genome-wide screening for genes whose deletion induces FTY720-sensitive growth in S. pombe and identified 49 genes. These gene products are related to the biological processes involved in metabolic processes, transport, transcription, translation, chromatin organization, cytoskeleton organization and intracellular signal transduction. Notably, most of the FTY720-sensitive deletion cells exhibited NAC-remedial FTY720 sensitivities and dysregulated ROS homeostasis. Our results revealed a novel gene network involving ROS homeostasis and the possible mechanisms of the FTY720 toxicity.
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PMID:A genome-wide screen for FTY720-sensitive mutants reveals genes required for ROS homeostasis. 2923 68