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：
10332379
负责人：
Seth Michael Rubin
金额：
$ 165.9万
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/10332379
关键词：
Automobile Driving Binding Binding Sites Breast Cancer Treatment CCNE1 gene 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 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 RB1 gene Recurrence Regulation Retinoblastoma Retinoblastoma Protein S phase Series Signal Transduction Structural Biochemistry Systems Biology Technology Testing Therapeutic Tumor Suppressor Proteins Work base cancer cell cancer genetics cancer therapy cancer type cell growth 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 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.

总体总结 Cyclin D-Cdk4/6-Rb-E2F 通路整合外部和内部信号来控制细胞周期进程在细胞周期的 G1/S 转变期间，细胞周期蛋白 D-Cdk4/6-Rb-E2F 途径的改变广泛存在。大多数人类癌症。这些改变被认为会增加癌细胞的增殖潜力。例如，视网膜母细胞瘤 (RB1) 肿瘤抑制因子的功能失活或简单来说，细胞周期蛋白 D 基因是多种人类癌症发展过程中反复出现的事件。共识模型，视网膜母细胞瘤蛋白 Rb 在细胞周期的 G1/S 转变时抑制细胞增殖 Rb 通过结合和抑制 E2F 转录因子来响应细胞生长和增殖信号。在正常细胞中，一系列细胞周期蛋白依赖性激酶复合物（第一个细胞周期蛋白 Rb 的 D-Cdk4/6 和 Cyclin E/A-Cdk2 磷酸化导致 Rb 从 E2F 解离。转录因子从而引起对 DNA 合成和其他关键方面重要的基因的转录因此，具有组成性失活的 Rb 的癌细胞被认为获得了增加。对正常细胞和癌细胞中细胞周期蛋白 D-Cdk4/6-Rb-E2F 通路的了解导致了开发已被批准用于治疗乳腺癌的特定 Cdk4/6 抑制剂正在针对其他几种癌症类型进行临床试验。在该范例中，抑制 Cdk4/6 会导致 Rb 减少。磷酸化，激活 Rb 的细胞周期抑制功能，但许多肿瘤对此没有反应。这些抑制剂的作用或只是暂时的，最近对患者和临床前模型的观察表明。我们对 Rb 通路的理解并不像我们之前想象的那么完整，这可以解释这个变量。该提案的总体目标是获得更深入的结构、分子、临床结果。和细胞对 Rb 通路的理解，最终目标是帮助设计新的和改进的治疗方法针对广泛癌症患者的这一途径的策略我们的首要目标是确定核心。调节 Cyclin D-Cdk4/6-Rb-E2F 通路的机制，包括 Cyclin D-Cdk4/6 如何磷酸化 Rb 以及以前未知的翻译后修饰如何调节 Rb 和 E2F 活性。目标是识别和研究 Rb 通路组件的新功能，包括 Cyclin D- 的新靶点 Cdk4/6 激酶、Rb 及其家族成员 p107 和 p130 的新功能以及新的调控机制我们的第三个目标是控制 E2F 转录因子的浓度和活性。以创新方式靶向 Rb 通路的策略，包括抑制 Cyclin D-Rb 的分子这些目标包括关联、刺激 p107 和 p130 的肿瘤抑制活性以及操纵 E2F 稳定性。将通过综合、协同和多学科方法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靶向 Cyclin D-Cdk4/6-Rb- 的新方法。 E2F 途径改善癌症治疗。