Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability
Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability
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DOI：
10.1074/jbc.273.23.14424
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发表时间：
1998-06-05
影响因子：
4.8
通讯作者：
Ferrari, S
中科院分区：
文献类型：
--
作者：
Hashemolhosseini, S;Nagamine, Y;Ferrari, S
免疫抑制剂雷帕霉素此前已被证明通过延长细胞周期的G_1期来抑制几种细胞类型的G(1)/S转变。这一过程似乎部分地受雷帕霉素敏感的FK506结合蛋白-雷帕霉素相关蛋白-p70 S6激酶(p70(S6K))通路和细胞周期蛋白依赖蛋白(CDK)的控制。我们现在发现，在血清刺激的NIH3T3细胞中，雷帕霉素处理延缓了细胞周期蛋白D1mRNA的积累。雷帕霉素似乎也会影响转录本的稳定性。药物的转录和转录后效应的综合作用最终导致细胞周期蛋白D1蛋白水平降低。此外，新合成的Cyclin D1蛋白的降解被雷帕霉素加速，这个过程可以通过包含蛋白酶体抑制剂N-乙酰-亮氨酸-去亮氨酸来阻止。雷帕霉素对细胞周期蛋白D1的整体作用进而导致与CDK4活性复合体的形成受阻，这一过程触发了p27(Kip1)抑制剂对细胞周期蛋白E/CDK2的重定向作用。鉴于这一新的实验证据，我们讨论了雷帕霉素诱导细胞周期停滞于G(1)/S转变的可能机制。
The immunosuppressant rapamycin has been shown previously to inhibit the G(1)/S transition in several cell types by prolonging the G, phase of the cell cycle. This process appears to be controlled in part, by the rapamycin-sensitive FK506-binding protein-rapamycin-associated protein-p70 S6 kinase (p70(S6k)) pathway and the cyclin-dependent kinases (Cdk). We now show that in serum-stimulated NIH 3T3 cells, rapamycin treatment delays the accumulation of cyclin D1 mRNA during progression through G,. Rapamycin also appears to affect stability of the transcript. The combined transcriptional and post-transcriptional effects of the drug ultimately result in decreased levels of cyclin D1 protein. Moreover, degradation of newly synthesized cyclin D1 protein is accelerated by rapamycin, a process prevented by inclusion of the proteasome inhibitor, N-acetyl-Leu-Leu-norleucinal. The overall effect of rapamycin on cyclin D1 leads, in turn, to impaired formation of active complexes with Cdk4, a process which triggers retargeting of the p27(Kip1) inhibitor to cyclin E/Cdk2. In view of this novel experimental evidence, we discuss a possible mechanism for the rapamycin-induced cell cycle arrest at the G(1)/S transition.