Brown E J, Albers M W, Shin T B, Ichikawa K, Keith C T, Lane W S, Schreiber S L
Department of Chemistry, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138.
Nature. 1994 Jun 30;369(6483):756-8. doi: 10.1038/369756a0.
The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly, these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases.
结构相关的天然产物雷帕霉素和FK506与同一细胞内受体FKBP12结合，但形成的复合物会干扰不同的信号通路。FKBP12-雷帕霉素可抑制骨肉瘤、肝脏和T细胞以及酵母细胞周期G1期的进程，并干扰参与G1期进程的促有丝分裂信号通路，即干扰蛋白p70S6k（参考文献5、11-13）和细胞周期蛋白依赖性激酶的激活。在此，我们分离出一种哺乳动物FKBP-雷帕霉素相关蛋白（FRAP），其与结合FKBP12的雷帕霉素结构变体的结合与这些配体抑制细胞周期进程的能力相关。从纯化的牛FRAP中获得的肽序列被用于分离一个与酿酒酵母的DRR1/TOR1和DRR2/TOR2基因产物高度相关的人cDNA克隆。尽管此前尚未证明DRR/TOR基因产物中的任何一种能直接结合FKBP-雷帕霉素复合物，但这些酵母基因在遗传上与雷帕霉素敏感途径相关，并且被认为编码脂质激酶。
