Luo Y, Marx S O, Kiyokawa H, Koff A, Massagué J, Marks A R
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Mol Cell Biol. 1996 Dec;16(12):6744-51. doi: 10.1128/MCB.16.12.6744.
The potent antiproliferative activity of the macrolide antibiotic rapamycin is known to involve binding of the drug to its cytosolic receptor, FKBP12, and subsequent interaction with targets of rapamycin, resulting in inhibition of p70 S6 kinase (p70S6K). However, the downstream events that lead to inhibition of cell cycle progression remain to be elucidated. The antiproliferative effects of rapamycin are associated with prevention of mitogen-induced downregulation of the cyclin-dependent kinase inhibitor p27Kip1, suggesting that the latter may play an important role in the growth pathway targeted by rapamycin. Murine BC3H1 cells, selected for resistance to growth inhibition by rapamycin, exhibited an intact p70S6K pathway but had abnormally low p27 levels that were no longer responsive to mitogens or rapamycin. Fibroblasts and T lymphocytes from mice with a targeted disruption of the p27Kip1 gene had impaired growth-inhibitory responses to rapamycin. These results suggest that the ability to regulate p27Kip1 levels is important for rapamycin to exert its antiproliferative effects.
已知大环内酯类抗生素雷帕霉素具有强大的抗增殖活性，其作用机制包括药物与胞质受体FKBP12结合，随后与雷帕霉素靶点相互作用，从而抑制p70 S6激酶（p70S6K）。然而，导致细胞周期进程抑制的下游事件仍有待阐明。雷帕霉素的抗增殖作用与预防丝裂原诱导的细胞周期蛋白依赖性激酶抑制剂p27Kip1下调有关，这表明后者可能在雷帕霉素靶向的生长途径中起重要作用。经选择对雷帕霉素生长抑制具有抗性的小鼠BC3H1细胞，其p70S6K途径完整，但p27水平异常低，且不再对丝裂原或雷帕霉素产生反应。来自p27Kip1基因靶向破坏小鼠的成纤维细胞和T淋巴细胞对雷帕霉素的生长抑制反应受损。这些结果表明，调节p27Kip1水平的能力对于雷帕霉素发挥其抗增殖作用很重要。
