Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation
Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation
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DOI：
10.1002/j.1460-2075.1996.tb00398.x
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发表时间：
1996-02-01
期刊：
影响因子：
11.4
通讯作者：
Sonenberg, N
中科院分区：
文献类型：
--
作者：
Beretta, L;Gingras, AC;Sonenberg, N
免疫抑制剂雷帕霉素在哺乳动物细胞和酵母中阻断细胞周期在G(1)期的进展。在此我们表明，雷帕霉素抑制NIH 3T3细胞中依赖帽子结构的翻译，但不抑制不依赖帽子结构的翻译。通过体外翻译实验确定，从雷帕霉素处理的细胞中提取的物质中依赖帽子结构的翻译也特异性降低。这种抑制与4E - BP1的去磷酸化以及随后的激活有因果关系，4E - BP1是一种最近被确定为帽子结合蛋白eIF - 4E功能抑制因子的蛋白质。雷帕霉素的这些作用是特异性的，因为雷帕霉素的结构类似物FK506对依赖帽子结构的翻译或4E - BP1的磷酸化均无影响。雷帕霉素 - FK506结合蛋白复合物是4E - BP1磷酸化抑制的效应物，因为FK506相对于雷帕霉素过量时可逆转雷帕霉素介导的4E - BP1磷酸化抑制。因此，eIF - 4E的失活至少在一定程度上是雷帕霉素处理的细胞中依赖帽子结构的翻译受抑制的原因。此外，这些结果表明4E - BP1的磷酸化是由FRAP/TOR信号通路介导的。
The immunosuppressant drug rapamycin blocks progression of the cell cycle at the G(1) phase in mammalian cells and yeast. Here we show that rapamycin inhibits cap-dependent, but not cap-independent, translation in NIH 3T3 cells. Cap-dependent translation is also specifically reduced in extracts from rapamycin-treated cells, as determined by in vitro translation experiments. This inhibition is causally related to the dephosphorylation and consequent activation of 4E-BP1, a protein recently identified as a repressor of the cap-binding protein, eIF-4E, function. These effects of rapamycin are specific as FK506, a structural analogue of rapamycin, had no effect on either cap-dependent translation or 4E-BP1 phosphorylation. The rapamycin-FK506 binding protein complex is the effector of the inhibition of 4E-BP1 phosphorylation as excess of FK506 over rapamycin reversed the rapamycin-mediated inhibition of 4E-BP1 phosphorylation. Thus, inactivation of eIF-4E is, at least in part, responsible for inhibition of cap-dependent translation in rapamycin-treated cells. Furthermore, these results suggest that 4E-BP1 phosphorylation is mediated by the FRAP/TOR signalling pathway.