Deciphering the mechanism of non-canonical cell cycle entry

破译非规范细胞周期进入机制

• 批准号: 10587052
• 负责人: Hee Won Yang
• 金额: $ 34.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587052
• 关键词: Abnormal Cell; Binding; Biochemical; Bypass; CDK2 gene; CDK4 gene; Cancer Intervention; Cell Cycle; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cell physiology; Cells; Classification; Clinical; Data; Degenerative Disorder; Deubiquitinating Enzyme; Development; E2F transcription factors; Event; Fostering; Foundations; Gene Expression; Genetic; Genetic Transcription; Goals; Health; Heterogeneity; Human; Imaging technology; In Vitro; Investigation; Left; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Methodology; Mission; Molecular; Mutation; National Institute of General Medical Sciences; Organism; Outcome; Outcomes Research; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Population; Post-Translational Protein Processing; Process; Protein Family; Proteins; Public Health; Regulation; Reporter; Reporting; Research; Resistance; Retinoblastoma Protein; Role; Signal Transduction; Stress; Testing; Tissues; Tumor Suppressor Genes; Ubiquitin; c-myc Genes; cancer cell; cancer type; cdc Genes; cellular imaging; developmental disease; genetic approach; human disease; in vivo; inhibitor; inhibitor therapy; innovation; insight; multicatalytic endopeptidase complex; new therapeutic target; novel; novel therapeutic intervention; pharmacologic; programs; protein activation; protein degradation; protein expression; response; sensor; single cell technology; success; ubiquitin isopeptidase; ubiquitin-protein ligase

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.

标题：解读非典型细胞周期进入机制 项目摘要 决定进入细胞周期是一个基本的细胞过程，是至关重要的发展和组织 维持，该过程的失调是癌症发展的原因。开始 细胞周期由细胞周期蛋白依赖性激酶4和6（CDK 4/6）调节，CDK 4/6由促有丝分裂信号激活。 激活突变通常存在于癌细胞中的促有丝分裂信号传导中，导致癌细胞的过度激活。 CDK 4/6和异常细胞增殖。因此，特异性CDK 4/6抑制剂显示出作为治疗的巨大前景 治疗各种癌症除了经典的CDK 4/6依赖性途径外， 表明哺乳动物细胞可以在CDK 4/6活性缺失的情况下进入细胞周期。虽然 CDK 4/6调节细胞周期进入的机制已经建立， 非典型细胞周期进入仍然难以捉摸。研究计划的目的是确定 细胞周期进入的非经典途径的机制。考虑到细胞间的异质性和细胞内 细胞周期进入的相互关联的调节过程，阐明哺乳动物细胞如何以及何时绕过 CDK 4/6并进入细胞周期是具有挑战性的。为了克服这些挑战，我们将应用活细胞传感器， 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来操纵非典型细胞周期进入的潜在调节剂。 我们的初步数据指出了一个理论机制，为非典型细胞周期的进入，可能在第一次出现， 自相矛盾的是：一个通常被CDK 4/6灭活的肿瘤抑制基因在细胞周期中被降解。 对持续的CDK 4/6抑制的应答，从而提供进入非典型细胞周期的手段。此外，委员会认为， 我们的初步数据表明，在这一过程的调节中有多种因素，它们之间存在着动态的相互作用 进一步整合外在和内在信号以控制非典型细胞周期进入的因子。 这项研究的完成将为细胞周期进入的动态调节提供新的见解， 对哺乳动物细胞中CDK 4/6抑制的适应性有了更深入的了解。此外，作为非典型 细胞周期进入严重限制了CDK 4/6抑制剂治疗癌症的成功， 研究有可能导致针对癌症细胞周期的新的治疗干预。