Hashemolhosseini S, Nagamine Y, Morley S J, Desrivières S, Mercep L, Ferrari S
Institute for Experimental Cancer Research, Tumor Biology Center, P. O. Box 1120, 79011 Freiburg, Germany.
J Biol Chem. 1998 Jun 5;273(23):14424-9. doi: 10.1074/jbc.273.23.14424.
The immunosuppressant rapamycin has been shown previously to inhibit the G1/S transition in several cell types by prolonging the G1 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 G1. 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 G1/S transition.
免疫抑制剂雷帕霉素此前已被证明可通过延长细胞周期的G1期来抑制多种细胞类型中的G1/S转换。这一过程似乎部分受雷帕霉素敏感的FK506结合蛋白-雷帕霉素相关蛋白-p70 S6激酶（p70(S6k)）途径和细胞周期蛋白依赖性激酶（Cdk）的控制。我们现在表明，在血清刺激的NIH 3T3细胞中，雷帕霉素处理会延迟细胞在G1期进程中细胞周期蛋白D1 mRNA的积累。雷帕霉素似乎也会影响转录本的稳定性。该药物的转录和转录后联合作用最终导致细胞周期蛋白D1蛋白水平降低。此外，雷帕霉素会加速新合成的细胞周期蛋白D1蛋白的降解，加入蛋白酶体抑制剂N-乙酰-亮氨酰-亮氨酰-正亮氨酸可阻止这一过程。雷帕霉素对细胞周期蛋白D1的总体作用进而导致与Cdk4形成活性复合物的过程受损，这一过程会触发p27(Kip1)抑制剂重新靶向细胞周期蛋白E/Cdk2。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在G1/S转换处停滞的可能机制。
