The Cdk-Rb-E2F pathway integrates external and internal signals to control progression at the G1/S transition of the mammalian cell cycle. Alterations in this pathway are found in most human cancers, and specific cyclin-dependent kinase Cdk4/6 inhibitors are approved or in clinical trials for the treatment of diverse cancers. In the long-standing paradigm for G1/S control, Cdks inactivate the retinoblastoma tumor suppressor protein (Rb) through phosphorylation, which releases E2F transcription factors to drive cell-cycle progression from G1 to S. However, recent observations in the laboratory and clinic challenge central tenets of the current paradigm and demonstrate that our understanding of the Rb pathway and G1/S control is still incomplete. Here, we integrate these new findings with the previous paradigm to synthesize a current molecular and cellular view of the mammalian G1/S transition. A more complete and accurate understanding of G1/S control will lead to improved therapeutic strategies targeting the cell cycle in cancer.

Cdk-Rb-E2F 通路整合了外部和内部信号，以控制哺乳动物细胞周期 G1/S 过渡的进程。在大多数人类癌症中都发现了该途径的改变，并且特定的细胞周期蛋白依赖性激酶 Cdk4/6 抑制剂已被批准或正在临床试验中用于治疗多种癌症。在 G1/S 控制的长期范式中，Cdks 通过磷酸化使视网膜母细胞瘤肿瘤抑制蛋白 (Rb) 失活，从而释放 E2F 转录因子以驱动细胞周期从 G1 进展到 S。然而，最近在实验室和临床中的观察挑战当前范式的中心原则，并证明我们对 Rb 通路和 G1/S 控制的理解仍然不完整。这里，我们将这些新发现与之前的范例相结合，以合成哺乳动物 G1/S 过渡的当前分子和细胞视图。对 G1/S 控制的更完整和准确的理解将导致针对癌症细胞周期的改进治疗策略。