Determining and targeting mechanisms controlling cancer cell division

确定和靶向控制癌细胞分裂的机制

基本信息

批准号：
10597160
负责人：
Seth Michael Rubin
金额：
$ 140.64万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-25 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597160
关键词：
Automobile Driving Binding Binding Sites Breast Cancer Treatment CCNE1 gene Cancer Control Cancer Patient Cell Cycle Cell Cycle Kinetics Cell Cycle Progression Cell Cycle Regulation Cell Proliferation Cell division Cells Cellular biology Clinic Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Consensus Cyclin D1 Cyclin-Dependent Kinases DNA DNA biosynthesis Development Dissociation E2F transcription factors Event Family member G1 Phase G1/S Transition Genes Genetic Transcription Goals Human Inhibition of Cell Proliferation Investigation Knowledge Malignant Neoplasms Measures Medicine Modeling Molecular Normal Cell Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Post-Translational Protein Processing Pre-Clinical Model Program Research Project Grants Proliferating Proteomics Recurrence Regulation Retinoblastoma Protein S phase Series Signal Transduction Structural Biochemistry Systems Biology Technology Testing Therapeutic Tumor Suppressor Proteins Work cancer cell cancer genetics cancer therapy cancer type cell growth cell preparation design experimental study genome editing imaging approach improved inhibitor innovation insight interdisciplinary approach kinase inhibitor molecular imaging novel novel strategies novel therapeutic intervention programs protein protein interaction response retinoblastoma tumor suppressor structural biology success targeted treatment tumor

项目摘要

OVERALL SUMMARY The Cyclin D-Cdk4/6-Rb-E2F pathway integrates external and internal signals to control cell cycle progression at the G1/S transition of the cell cycle. Alterations in the Cyclin D-Cdk4/6-Rb-E2F pathway are found in the vast majority of human cancers. These alterations are thought to increase the proliferative potential of cancer cells. For example, the functional inactivation of the retinoblastoma (RB1) tumor suppressor or the amplification of Cyclin D genes is a recurrent event in the development of a wide range of human cancers. In the simple consensus model, the retinoblastoma protein Rb inhibits cell proliferation at the G1/S transition of the cell cycle by binding and inhibiting E2F transcription factors. In response to cell growth and proliferative signals, Rb is phosphorylated and inactivated in normal cells by a series of Cyclin-dependent kinase complexes (first Cyclin D-Cdk4/6 and then Cyclin E/A-Cdk2). Phosphorylation of Rb results in the dissociation of Rb from E2F transcription factors thereby causing transcription of genes important for DNA synthesis and other key aspects of cell cycle progression. Thus, cancer cells with constitutively inactive Rb are thought to acquire an increased proliferative potential. Knowledge of the Cyclin D-Cdk4/6-Rb-E2F pathway in normal and cancer cells has led to the development of specific Cdk4/6 inhibitors that have been approved for the treatment of breast cancer and are in clinical trials for several other cancer types. In this paradigm, inhibition of Cdk4/6 results in decreased Rb phosphorylation, which activates Rb’s cell cycle inhibitory function. However, many tumors do not respond to these inhibitors or do so only transiently. Recent observations in patients and pre-clinical models indicate that our understanding of the Rb pathway is not as complete as we previously thought. This may explain the variable results of Cdk4/6 inhibitors in the clinic. The overall goal of this proposal is to gain a deeper structural, molecular, and cellular understanding of the Rb pathway with the ultimate goal to help design new and improved therapeutic strategies targeting this pathway in a broad range of cancer patients. Our first goal is to determine the core mechanisms regulating the Cyclin D-Cdk4/6-Rb-E2F pathway, including how Cyclin D-Cdk4/6 phosphorylates Rb and how previously unknown post-translational modifications regulate Rb and E2F activities. Our second goal is to identify and investigate new functions of Rb pathway components, including new targets of Cyclin D- Cdk4/6 kinases, new functions for Rb and its family members p107 and p130, and new regulatory mechanisms controlling the concentration and activity of E2F transcription factors. Our third goal is to initiate the development of strategies that target the Rb pathway in innovative ways, including molecules that inhibit Cyclin D-Rb association, stimulate the tumor suppressor activity of p107 and p130, and manipulate E2F stability. These goals will be achieved in three inter-related Projects via a comprehensive, synergistic and multi-disciplinary approach. Ultimately, the information gained from these studies may provide new ways to target the Cyclin D-Cdk4/6-Rb- E2F pathway to improve cancer therapy.

总结细胞周期蛋白D-CDK4/6-RB-E2F途径集成了外部和内部信号，以控制细胞周期的进程在细胞周期的G1/s转变下。在疫苗中发现了细胞周期蛋白D-CDK4/6-RB-E2F途径的改变大多数人类癌症。这些改变被认为会增加癌细胞的增殖剂潜力。例如，视网膜母细胞瘤（RB1）肿瘤的功能失活或放大 Cyclin d基因是在广泛的人类癌症发展中的复发事件。简单共识模型，视网膜细胞瘤蛋白RB在细胞周期的G1/s转变下抑制细胞增殖通过结合和抑制E2F转录因子。响应细胞生长和增殖信号，RB为通过一系列细胞周期蛋白依赖性激酶复合物在正常细胞中磷酸化并灭活（首先细胞周期蛋白） D-CDK4/6，然后再经Cyclin E/A-CDK2）。 RB的磷酸化导致RB与E2F的解离转录因子，从而导致基因转录对于DNA合成和其他关键方面重要细胞周期进程。这就是人们认为，持续无活跃的RB的癌细胞获得了增加增殖潜力。对正常和癌细胞中的细胞周期蛋白D-CDK4/6-RB-E2F途径的了解已导致已批准用于治疗乳腺癌和的特定CDK4/6抑制剂的开发正在进行其他几种癌症类型的临床试验。在此范式中，抑制CDK4/6导致RB降低磷酸化，激活RB的细胞周期抑制功能。但是，许多肿瘤没有反应这些抑制剂或仅暂时进行。在患者和临床前模型中的最新观察表明，我们对RB途径的理解并不像以前想象的那么完整。这可以解释变量诊所中CDK4/6抑制剂的结果。该提议的总体目标是获得更深的结构，分子，以及对RB途径的细胞理解，其最终目标是帮助设计新的和改进的治疗针对这种途径的策略在广泛的癌症患者中。我们的第一个目标是确定核心调节细胞周期蛋白D-CDK4/6-RB-E2F途径的机制，包括Cyclin D-CDK4/6磷酸化的方式 RB以及以前未知的翻译后修改如何调节RB和E2F活动。我们的第二个目标是识别和研究RB途径成分的新功能，包括细胞周期蛋白D-的新目标 CDK4/6激酶，RB及其家人P107和P130的新功能以及新的调节机制控制E2F转录因子的浓度和活性。我们的第三个目标是启动发展以创新方式针对RB途径的策略，包括抑制细胞周期蛋白D-RB的分子关联，刺激p107和p130的肿瘤抑制活性，并操纵E2F稳定性。这些目标通过全面，协同和多学科的方法，将在三个相互关联的项目中实现。最终，从这些研究中获得的信息可能会提供针对细胞周期蛋白D-CDK4/6-RB-的新方法 E2F改善癌症治疗的途径。