Nourse J, Firpo E, Flanagan W M, Coats S, Polyak K, Lee M H, Massague J, Crabtree G R, Roberts J M
Program in Cancer Biology, Stanford University Medical School, California 94305.
Nature. 1994 Dec 8;372(6506):570-3. doi: 10.1038/372570a0.
The cyclin-dependent kinase (Cdk) enzymes, when associated with the G1 cyclins D and E, are rate-limiting for entry into the S phase of the cell cycle. During T-cell mitogenesis, antigen-receptor signalling promotes synthesis of cyclin E and its catalytic partner, Cdk2, and interleukin-2 (IL-2) signalling activates cyclin E/Cdk2 complexes. Rapamycin is a potent immunosuppressant which specifically inhibits G1-to-S-phase progression, leading to cell-cycle arrest in yeast and mammals. Here we report that IL-2 allows Cdk activation by causing the elimination of the Cdk inhibitor protein p27Kip1, and that this is prevented by rapamycin. By contrast, the Cdk inhibitor p21 is induced by IL-2 and this induction is blocked by rapamycin. Our results show that p27Kip1 governs Cdk activity during the transition from quiescence to S phase in T lymphocytes and that p21 function may be restricted to cycling cells.
细胞周期蛋白依赖性激酶（Cdk）与G1期细胞周期蛋白D和E结合时，是细胞周期进入S期的限速因素。在T细胞有丝分裂过程中，抗原受体信号传导促进细胞周期蛋白E及其催化伴侣Cdk2的合成，而白细胞介素-2（IL-2）信号传导激活细胞周期蛋白E/Cdk2复合物。雷帕霉素是一种强效免疫抑制剂，可特异性抑制从G1期到S期的进程，导致酵母和哺乳动物细胞周期停滞。我们在此报告，IL-2通过促使Cdk抑制蛋白p27Kip1消除来激活Cdk，而雷帕霉素可阻止这一过程。相反，Cdk抑制剂p21由IL-2诱导，且这种诱导被雷帕霉素阻断。我们的结果表明，p27Kip1在T淋巴细胞从静止期向S期转变过程中调控Cdk活性，并且p21的功能可能仅限于正在进行细胞周期循环的细胞。
