Deciphering the mechanism of non-canonical cell cycle entry

破译非规范细胞周期进入机制

基本信息

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
项目类别：
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

项目摘要

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：破译非规范细胞周期进入机制项目概要进入细胞周期的决定是一个基本的细胞过程，对于发育和组织至关重要维持，这一过程的失调是癌症发生的原因。发起细胞周期由细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 调节，该激酶由有丝分裂信号传导激活。激活突变常见于癌细胞的有丝分裂信号传导中，导致过度激活 CDK4/6 与异常细胞增殖。因此，特定的 CDK4/6 抑制剂作为治疗方法显示出巨大的前景用于各种类型的癌症。除了典型的 CDK4/6 依赖性途径外，新出现的证据表明哺乳动物细胞可以在缺乏 CDK4/6 活性的情况下进入细胞周期。虽然 CDK4/6 调节细胞周期进入的机制已明确，其分子机制非规范的细胞周期进入仍然难以捉摸。拟议研究计划的目标是确定进入细胞周期的非典型途径的机制。鉴于细胞间的异质性和高度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 CDK4/6并进入细胞周期具有挑战性。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。我们还将利用各种操纵非规范细胞周期进入的潜在调节剂的药理学和遗传学方法。我们的初步数据指出了可能首先出现的非规范细胞周期进入的理论机制矛盾的是：通常被 CDK4/6 灭活的肿瘤抑制基因在对持续 CDK4/6 抑制的反应，从而提供一种进入非典型细胞周期的方法。而且，我们的初步数据表明该过程的调节涉及多种因素，表明存在动态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。完成拟议的研究将为细胞周期进入和进入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，作为非规范进入细胞周期严重限制了 CDK4/6 抑制剂治疗癌症的成功，建议的结果研究有可能带来针对癌症细胞周期的新型治疗干预措施。