Kuo C J, Chung J, Fiorentino D F, Flanagan W M, Blenis J, Crabtree G R
Howard Hughes Medical Institute, Unit in Molecular and Genetic Medicine, Beckman Center, Stanford University School of Medicine, California 94305-5425.
Nature. 1992 Jul 2;358(6381):70-3. doi: 10.1038/358070a0.
The macrolide rapamycin induces cell cycle G1 arrest in yeast and in mammalian cells, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases. Rapamycin completely and rapidly inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase at concentrations comparable to those blocking S phase entry of T cells (0.05-0.2 nM). The structurally related macrolide FK506 competitively antagonizes the actions of rapamycin, indicating that these effects are mediated by FKBP, which binds the transition-state mimic structure common to both rapamycin and FK506 (refs 4, 6, 9-11). The selective blockade of the p70 S6 kinase activation cascade by the rapamycin-FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.
大环内酯类药物雷帕霉素可诱导酵母和哺乳动物细胞的细胞周期G1期停滞，这表明存在一条进化上保守的、对雷帕霉素敏感的途径可能调控细胞进入S期。在哺乳动物中，雷帕霉素抑制白细胞介素-2受体诱导的S期进入及随后的T细胞增殖，从而导致免疫抑制。我们在此表明，白细胞介素-2选择性地刺激p70 S6激酶的磷酸化和激活，但不刺激erk编码的丝裂原活化蛋白激酶（MAP激酶）和rsk编码的S6激酶。雷帕霉素在与阻断T细胞进入S期（0.05 - 0.2 nM）相当的浓度下，能完全且迅速地抑制白细胞介素-2诱导的p70 S6激酶的磷酸化和激活。结构相关的大环内酯类药物FK506竞争性拮抗雷帕霉素的作用，表明这些效应是由FKBP介导的，FKBP能结合雷帕霉素和FK506共有的过渡态模拟结构（参考文献4、6、9 - 11）。雷帕霉素 - FKBP复合物对p70 S6激酶激活级联的选择性阻断表明该信号通路参与调控T细胞进入S期。
