Genetic, Biochemical, and Transcriptional Responses of Saccharomyces cerevisiae to the Novel Immunomodulator FTY720 Largely Mimic Those of the Natural Sphingolipid Phytosphingosine*
Genetic, Biochemical, and Transcriptional Responses of Saccharomyces cerevisiae to the Novel Immunomodulator FTY720 Largely Mimic Those of the Natural Sphingolipid Phytosphingosine*
复制标题
酿酒酵母对新型免疫调节剂 FTY720 的遗传、生化和转录反应在很大程度上模仿了天然鞘脂植物鞘氨醇*
DOI：
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发表时间：
2004
影响因子：
4.8
通讯作者：
N. Movva
中科院分区：
文献类型：
--
作者：
Carole A. Welsch;Lukas Roth;J. Goetschy;N. Movva
Sphingolipids are signaling molecules that influence diverse cellular functions from control of the cell cycle to degradation of plasma membrane proteins. The synthetic sphingolipid-like compound FTY720 is an immunomodulating agent in clinical trials for transplant graft maintenance. In this report, we compare the effects of the natural yeast sphingolipid phytosphingosine with FTY720 in Saccharomyces cerevisiae. We show that the multicopy suppressor genes that induce growth resistance to FTY720 also confer resistance to growth-inhibitory concentrations of phytosphingosine. In addition, mutants for ubiquitination pathway proteins are shown to be resistant to the growth-inhibiting effect of both FTY720 and phytosphingosine. We observe fewer similarities between sphingosine and FTY720 than between FTY720 and phytosphingosine as revealed by genetic studies. Yeast cells lacking the specific sphingosine kinase LCB4 are sensitive to phytosphingosine and FTY720 but resistant to sphingosine, suggesting that FTY720 and phytosphingosine have a more related mechanism of action. Gene expression profile comparisons of sensitive and resistant yeast cells exposed to FTY720 and phytosphingosine highlight a number of similarities. In response to treatment with these compounds, ∼77% of the genes that are regulated >2-fold by FTY720 also respond to phytosphingosine in the same direction in the parent strain. In addition, a close inspection of TAT1 and TAT2 transporters following exposure to phytosphingosine indicates that TAT1 protein is degraded in a similar fashion upon treatment with FTY720 and phytosphingosine. There were differences, however, with respect to the TAT2 protein level and the expression profiles of a subset of genes. The genetic, transcriptional, and biochemical data together indicate that FTY720 and phytosphingosine influence similar pathways in yeast cells. These findings offer further insights into the physiological pathways influenced by these compounds in all eukaryotic cells and help us to understand the therapeutic consequences of FTY720 in humans.
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影响因子：
0.9
作者：
B. Kahan
通讯作者：
B. Kahan
磷酸化鞘氨醇长链碱基的积累导致酿酒酵母细胞生长受到抑制。
影响因子：
3.3
作者：
Kim,S;Fyrst,H;Saba,J
通讯作者：
Saba,J
影响因子：
3.3
作者：
Gasch, AP;Spellman, PT;Brown, PO
通讯作者：
Brown, PO
DOI：
10.1073/pnas.89.15.6746
发表时间：
1992-08-01
影响因子：
11.1
作者：
DAIGNANFORNIER, B;FINK, GR
通讯作者：
FINK, GR