A MAMMALIAN PROTEIN TARGETED BY G1-ARRESTING RAPAMYCIN-RECEPTOR COMPLEX
A MAMMALIAN PROTEIN TARGETED BY G1-ARRESTING RAPAMYCIN-RECEPTOR COMPLEX
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DOI：
10.1038/369756a0
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发表时间：
1994-06-30
期刊：
影响因子：
64.8
通讯作者：
SCHREIBER, SL
中科院分区：
文献类型：
--
作者：
BROWN, EJ;ALBERS, MW;SCHREIBER, SL
结构相关的天然产物雷帕霉素和FK506与相同的细胞内受体FKBP12结合，但产生的复合物干扰不同的信号通路（1,2）。FKBP12-雷帕霉素在骨肉瘤(3)、肝（4,5）和T细胞（6,7）以及酵母中抑制细胞周期G1期的进展，并干扰参与G1进展的有丝分裂信号通路（9,10），即激活蛋白p70(S6k)（参考文献5,11 -13）和周期蛋白依赖性激酶（3,14-16）。在这里，我们分离了一种哺乳动物fkbp -雷帕霉素相关蛋白（FRAP），其与雷帕霉素结构变体的结合与FKBP12复合物的结合与这些配体抑制细胞周期进展的能力相关。利用纯化牛FRAP的肽序列分离出与酿酒酵母DRR1/TOR1和DRR2/TOR2基因产物高度相关的人cDNA克隆（8,17,18）。虽然之前没有证据表明DRR/TOR基因产物可以直接结合fkbp -雷帕霉素复合物（17,19），但这些酵母基因与雷帕霉素敏感通路有遗传联系，并被认为编码脂质激酶（17-20）。
THE structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways(1,2). FKBP12- rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma(3), liver(4,5) and T cells(6,7) as well as in yeasts, and interferes with mitogenic signalling pathways that are involved in G1 progressiong(9,10), namely with activation of the protein p70(S6k) (refs 5, 11-13) and cyclin-dependent kinases(3,14-16). 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(8,17,18). Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly(17,19), these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases(17-20).