Sherr C J
Howard Hughes Medical Institute, Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Stem Cells. 1994;12 Suppl 1:47-55; discussion 55-7.
Mammalian D-type cyclins act as regulatory subunits of cyclin-dependent kinases (cdks) to form holoenzymes whose activities are both necessary and rate limiting for progression through the first gap phase (G1) of the cell cycle. D-type cyclins act as growth factor sensors to integrate receptor-mediated signals with the cell cycle machinery and to thereby enforce the decision of cells to enter their DNA synthetic (S) phase. Mitogenic and anti-proliferative stimuli affect the transcription of D-type cyclin genes and modulate both cyclin and cdk protein synthesis, their assembly into holoenzymes, post-translational modification, and serine/threonine kinase activity. In turn, the holoenzymes facilitate G1 exit by phosphorylating key cellular substrates, the retinoblastoma protein among them. Negative regulators of macrophage G1 progression, including cyclic AMP and the immunosuppressant rapamycin, extinguish the activity of G1 cyclin-dependent kinases by inducing novel polypeptide inhibitors that both inhibit the post-translational activation of cyclin-bound cdks and directly interfere with their catalytic functions. Our emerging understanding of G1 cyclins, their associated cdks, their proximal regulators, and their cdk substrates has now begun to provide a mechanistic understanding of how cells interpret mitogenic signals and make the decision to replicate their chromosomal DNA.
哺乳动物D型细胞周期蛋白作为细胞周期蛋白依赖性激酶（cdks）的调节亚基，形成全酶，其活性对于细胞周期的第一个间隙期（G1）的进程既是必需的，也是限速的。D型细胞周期蛋白作为生长因子传感器，将受体介导的信号与细胞周期机制整合起来，从而促使细胞决定进入DNA合成（S）期。有丝分裂原和抗增殖刺激影响D型细胞周期蛋白基因的转录，并调节细胞周期蛋白和cdk蛋白的合成、它们组装成全酶、翻译后修饰以及丝氨酸/苏氨酸激酶活性。反过来，全酶通过磷酸化关键的细胞底物（包括视网膜母细胞瘤蛋白）促进G1期退出。巨噬细胞G1期进程的负调节因子，包括环磷酸腺苷和免疫抑制剂雷帕霉素，通过诱导新的多肽抑制剂来消除G1期细胞周期蛋白依赖性激酶的活性，这些抑制剂既抑制细胞周期蛋白结合的cdks的翻译后激活，又直接干扰它们的催化功能。我们对G1期细胞周期蛋白、它们相关的cdks、它们的近端调节因子以及它们的cdk底物的新认识，现在已经开始为理解细胞如何解读有丝分裂原信号并决定复制其染色体DNA提供一个机制性的理解。
