Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan
Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan.
Open Biol. 2018 Mar;8(3). doi: 10.1098/rsob.170261.
Rapamycin inhibits TOR (target of rapamycin) kinase, and is being used clinically to treat various diseases ranging from cancers to fibrodysplasia ossificans progressiva. To understand rapamycin mechanisms of action more comprehensively, 1014 temperature-sensitive (ts) fission yeast () mutants were screened in order to isolate strains in which the ts phenotype was rescued by rapamycin. Rapamycin-rescued 45 strains, among which 12 genes responsible for temperature sensitivity were identified. These genes are involved in stress-activated protein kinase (SAPK) signalling, chromatin regulation, vesicle transport, and CoA- and mevalonate-related lipid metabolism. Subsequent metabolome analyses revealed that rapamycin upregulated stress-responsive metabolites, while it downregulated purine biosynthesis intermediates and nucleotide derivatives. Rapamycin alleviated abnormalities in cell growth and cell division caused by mutants (Δ) of SAPK. Notably, in Δ, rapamycin reduced greater than 75% of overproduced metabolites (greater than 2× WT), like purine biosynthesis intermediates and nucleotide derivatives, to WT levels. This suggests that these compounds may be the points at which the SAPK/TOR balance regulates continuous cell proliferation. Rapamycin might be therapeutically useful for specific defects of these gene functions.
雷帕霉素抑制 TOR（雷帕霉素的靶标）激酶，目前临床上正在用于治疗从癌症到骨化性纤维发育不良等各种疾病。为了更全面地了解雷帕霉素的作用机制，筛选了 1014 个温度敏感（ts）裂殖酵母（）突变体，以分离出 ts 表型可被雷帕霉素挽救的菌株。雷帕霉素挽救了 45 株菌株，其中鉴定出 12 个负责温度敏感性的基因。这些基因涉及应激激活蛋白激酶（SAPK）信号、染色质调节、囊泡运输以及 CoA 和甲羟戊酸相关的脂质代谢。随后的代谢组学分析表明，雷帕霉素上调了应激反应代谢物，同时下调了嘌呤生物合成中间产物和核苷酸衍生物。雷帕霉素缓解了 SAPK 突变体（Δ）引起的细胞生长和细胞分裂异常。值得注意的是，在Δ中，雷帕霉素将超过 75%的过量产生的代谢物（超过 2×WT），如嘌呤生物合成中间产物和核苷酸衍生物，降低到 WT 水平。这表明这些化合物可能是 SAPK/TOR 平衡调节连续细胞增殖的关键点。雷帕霉素可能对这些基因功能的特定缺陷具有治疗作用。
