Leone G, DeGregori J, Sears R, Jakoi L, Nevins J R
Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature. 1997 May 22;387(6631):422-6. doi: 10.1038/387422a0.
Considerable evidence points to a role for G1 cyclin-dependent kinase (CDK) in allowing the accumulation of E2F transcription factor activity and induction of the S phase of the cell cycle. Numerous experiments have also demonstrated a critical role for both Myc and Ras activities in allowing cell-cycle progression. Here we show that inhibition of Ras activity blocks the normal growth-dependent activation of G1 CDK, prevents activation of the target genes of E2F, and results in cell-cycle arrest in G1. We also show that Ras is essential for entry into the S phase in Rb+/+ fibroblasts but not in Rb-/- fibroblasts, establishing a link between Ras and the G1 CDK/Rb/E2F pathway. However, although expression of Ras alone will not induce G1 CDK activity or S phase, coexpression of Ras with Myc allows the generation of cyclin E-dependent kinase activity and the induction of S phase, coincident with the loss of the p27 cyclin-dependent kinase inhibitor (CKI). These results suggest that Ras, along with the activation of additional pathways, is required for the generation of G1 CDK activity, and that activation of cyclin E-dependent kinase in particular depends on the cooperative action of Ras and Myc.
大量证据表明，G1 细胞周期蛋白依赖性激酶（CDK）在促使 E2F 转录因子活性积累以及诱导细胞周期 S 期方面发挥作用。众多实验也已证明，Myc 和 Ras 活性在细胞周期进程中均起着关键作用。在此我们表明，抑制 Ras 活性会阻断 G1 CDK 的正常生长依赖性激活，阻止 E2F 靶基因的激活，并导致细胞周期在 G1 期停滞。我们还表明，Ras 对于 Rb+/+ 成纤维细胞进入 S 期至关重要，但对于 Rb-/- 成纤维细胞则并非如此，这在 Ras 与 G1 CDK/Rb/E2F 通路之间建立了联系。然而，尽管单独表达 Ras 不会诱导 G1 CDK 活性或 S 期，但 Ras 与 Myc 共表达会产生细胞周期蛋白 E 依赖性激酶活性并诱导 S 期，同时伴随着 p27 细胞周期蛋白依赖性激酶抑制剂（CKI）的丧失。这些结果表明，Ras 连同其他通路的激活是产生 G1 CDK 活性所必需的，并且细胞周期蛋白 E 依赖性激酶的激活尤其依赖于 Ras 和 Myc 的协同作用。
