FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line.
FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line.
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DOI：
10.1016/s0021-9258(18)41602-x
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发表时间：
1993-10
期刊：
影响因子：
--
通讯作者：
M. Albers;R. Williams;E. Brown;A. Tanaka;F. Hall;S. Schreiber
中科院分区：
文献类型：
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作者：
M. Albers;R. Williams;E. Brown;A. Tanaka;F. Hall;S. Schreiber
天然产物雷帕霉素（如结构相关的免疫抑制剂 FK506）进入细胞后，会与 FKBP 蛋白家族的成员结合。产生的一种或多种 FKBP-雷帕霉素复合物可阻断某些生长因子受体发出的信号传导途径。最近，添加雷帕霉素被证明可以抑制 70-kDa 核糖体 S6 蛋白激酶的磷酸化和激活，这种情况通常在某些细胞因子和生长因子受体激活后几分钟发生。我们现在报道，可以在向静止的人骨肉瘤细胞添加血清生长因子4至6小时后添加雷帕霉素，并且仍然将这些细胞阻滞在G1期。该作用窗口与细胞周期蛋白依赖性激酶 (cdk) 活性的诱导出现相关，并且添加雷帕霉素可抑制该活性的诱导。此外，p36cyclin D1 在未处理的细胞裂解物中与该 cdk 蛋白复合物结合，但在雷帕霉素处理的细胞裂解物中不与该 cdk 蛋白复合物结合。总之，这些研究表明，FKBP-雷帕霉素可以在 MG-63 人骨肉瘤细胞的 G1 早期调节细胞周期蛋白依赖性激酶活性和细胞周期蛋白 D1-cdk 关联。
Upon entering a cell the natural product rapamycin, like the structurally related immunosuppressant FK506, associates with members of the FKBP family of proteins. One or more of the resulting FKBP-rapamycin complexes blocks signaling pathways emanating from some growth factor receptors. Recently, the addition of rapamycin was shown to inhibit the phosphorylation and activation of a 70-kDa ribosomal S6 protein kinase, which normally occurs minutes after the activation of certain cytokine and growth factor receptors. We now report that rapamycin can be added 4 to 6 h after the addition of serum growth factors to quiescent human osteosarcoma cells and still arrest these cells in G1. This window of action correlates with the inducible appearance of a cyclin-dependent kinase (cdk) activity, and the induction of this activity is inhibited by the addition of rapamycin. Furthermore, p36cyclin D1 associates with this cdk protein complex in lysates of untreated cells, but does not associate with this cdk protein complex in lysates of rapamycin-treated cells. Together, these studies demonstrate that FKBP-rapamycin can modulate a cyclin-dependent kinase activity and a cyclin D1-cdk association during early G1 in MG-63 human osteosarcoma cells.