Deciphering the mechanism of non-canonical cell cycle entry

标题：破译非正则细胞周期进入机制 项目总结 进入细胞周期的决定是一个基本的细胞过程，对发育和组织至关重要 维持，这一过程的失调是癌症发展的原因。发起 细胞周期受细胞周期蛋白依赖性激酶4和6(CDK4/6)的调控，CDK4/6由有丝分裂信号激活。 激活突变通常在癌细胞的有丝分裂信号中被发现，导致过度激活 CDK4/6和细胞异常增殖。因此，特定的CDK4/6抑制剂显示出巨大的治疗前景。 治疗各种类型的癌症。除了典型的CDK4/6依赖途径外，新出现的证据 提示哺乳动物细胞可以在没有CDK4/6活性的情况下进入细胞周期。尽管 CDK4/6调节细胞周期进入的机制已经确立，其分子机制 非规范的细胞周期进入仍然难以捉摸。拟议的研究计划的目标是确定 细胞周期进入的非典型途径的机制。考虑到细胞间的异质性和高度的 细胞周期进入的相互关联的调控过程，阐明哺乳动物细胞如何以及何时旁路 而CDK4/6进入细胞周期是具有挑战性的。为了克服这些挑战，我们将把活细胞传感器应用于 CDK活性与我们创新的单细胞方法相结合。我们还将使用各种 药理学和遗传学方法，以操纵非规范细胞周期进入的潜在调节器。 我们的初步数据指出了一种非规范细胞周期进入的理论机制，这种机制最初可能会出现 矛盾：一种通常被CDK4/6灭活的肿瘤抑制基因被转送到 对持续的CDK4/6抑制做出反应，从而为非规范细胞周期进入提供了一种手段。此外， 我们的初步数据表明，在这一过程的调节中涉及多种因素，这表明了一种动态的相互作用 进一步整合外在和内在信号以控制非规范细胞周期进入的因素。 拟议研究的完成将为细胞周期进入和细胞周期的动态调节提供新的见解 更好地了解哺乳动物细胞对CDK4/6抑制的适应。此外，作为非规范的 细胞周期进入严重限制了CDK4/6抑制剂治疗癌症的成功，来自拟议的 研究有可能导致针对癌症细胞周期的新的治疗干预措施。

Title: Deciphering the mechanism of non-canonical cell cycle entry PROJECT SUMMARY The decision to enter the cell cycle is a fundamental cellular process that is critical to development and tissue maintenance, with dysregulation of this process being responsible for the development of cancer. Initiation of the cell cycle is regulated by cyclin-dependent kinase 4 and 6 (CDK4/6), which is activated by mitogenic signaling. Activating mutations are commonly found in mitogenic signaling in cancer cells, leading to overactivation of CDK4/6 and abnormal cell proliferation. Thus, specific CDK4/6 inhibitors show immense promise as treatments for various types of cancer. In addition to the canonical CDK4/6-dependent pathway, emerging evidence suggests that mammalian cells can enter the cell cycle in the absence of CDK4/6 activity. Although the mechanism by which CDK4/6 regulates cell cycle entry is well established, the molecular mechanisms underlying non-canonical cell cycle entry remain elusive. The objective of the proposed research program is to determine the mechanisms of the non-canonical pathway for cell cycle entry. Given cell-to-cell heterogeneity and the highly interconnected regulatory processes of cell cycle entry, elucidating how and when mammalian cells bypass CDK4/6 and enter the cell cycle is challenging. To overcome these challenges, we will apply live-cell sensors for CDK activity in combination with our innovative single-cell methodologies. We will also use a variety of pharmacological and genetic approaches to manipulate potential regulators of non-canonical cell cycle entry. Our preliminary data point to a theoretical mechanism for non-canonical cell cycle entry that may at first appear paradoxical: a tumor suppressor gene that is normally inactivated by CDK4/6 is routed for degradation in response to sustained CDK4/6 inhibition, thereby providing a means for non-canonical cell cycle entry. Moreover, our preliminary data implicate multiple factors in the regulation of this process, suggesting a dynamic interplay of factors that further integrates extrinsic and intrinsic signals to control non-canonical cell cycle entry. Completion of the proposed research will provide new insight into the dynamic regulation of cell cycle entry and a greater understanding of adaptations to CDK4/6 inhibition in mammalian cells. In addition, as non-canonical cell cycle entry severely limits the success of CDK4/6 inhibitor therapy in cancer, outcomes from the proposed research have the potential to lead to novel therapeutic interventions targeting the cell cycle in cancer.