The Anaphase Promoting Complex and Cell Cycle Exit

后期促进复合物和细胞周期退出

基本信息

批准号：
8292114
负责人：
NAGI G AYAD
金额：
$ 44.97万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292114
关键词：
Address Anaphase Brain CDH1 gene Cell Cycle Cell Cycle Regulation Cell Proliferation Cells Cerebellum Clinical Research Complex Defect Disease Enzymes Epithelial Cells Event F-Box Proteins Gene Deletion Goals Knockout Mice Mediating Metaphase Mitotic Mus Muscle Cells Names Nervous system structure Neuronal Differentiation Neurons Pathway interactions Phase Phosphorylation Phosphotransferases Proteins Research Screening procedure Testing Time Transgenic Organisms Ubiquitin-mediated Proteolysis Pathway Work anaphase-promoting complex base casein kinase I cell type cyclin-dependent kinase inhibitor 1B genome-wide granule cell in vitro activity in vivo inhibitor/antagonist lens malignant neurologic neoplasms medulloblastoma migration nervous system disorder neurogenesis novel precursor cell progenitor public health relevance small molecule subventricular zone ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Understanding neurogenesis is contingent upon elucidating cell cycle exit. An essential feature of all cell cycle transitions is their irreversibility. Once a commitment to enter a particular cell cycle phase is made, return to the previous phase is not possible. This is in part due to ubiquitin mediated proteolysis pathways that target substrates for proteasomal degradation. Ubiquitin mediated proteolysis pathways contain E1, E2, and E3 enzymes that regulate both the timing and fidelity of degradation events. One of the most important E3 enzymes is a multi-subunit complex named the Anaphase Promoting Complex, or APC. The APC controls both the metaphase to anaphase transition and mitotic exit. The APC is also active during cell cycle exit and differentiation of neuronal precursors. The APC degrades the ubiquitin ligase component Skp2, which allows p27kip1 levels to rise, thereby inducing cell cycle exit. The overall goal of this research is to test the hypothesis that ubiquitin mediated proteolysis controlled by the ubiquitin ligase the Anaphase Promoting Complex (APC) is required for cell cycle exit in the developing nervous system. PUBLIC HEALTH RELEVANCE: We are studying the mechanisms controlling neuronal precursor cell proliferation. These mechanisms are often misregulated in neurological diseases and cancers. Our work will identify both targets and small molecule inhibitors of cell cycle transitions, which can be used for both academic clinical researches to treat diseases such as medulloblastoma.

描述（由申请人提供）：理解神经发生取决于阐明细胞周期出口。所有细胞周期过渡的基本特征是它们的不可逆性。一旦做出了进入特定细胞周期阶段的承诺，就无法返回上一个阶段。这部分是由于泛素介导的蛋白水解途径靶向蛋白酶体降解。泛素介导的蛋白水解途径含有E1，E2和E3酶，可调节降解事件的时间和保真度。最重要的E3酶之一是一种多生成复合物，称为促进复合物或APC的多种基络合物。 APC同时控制了后期过渡和有丝分裂出口。在细胞周期出口和神经元前体的分化过程中，APC也具有活性。 APC降解了泛素连接酶成分SKP2，该SKP2允许P27KIP1水平上升，从而诱导细胞周期出口。这项研究的总体目的是检验以下假设：泛素介导的蛋白水解由泛素连接酶控制的蛋白水解促进复合体（APC）是发展神经系统中细胞周期退出所必需的。公共卫生相关性：我们正在研究控制神经元前体细胞增殖的机制。这些机制通常在神经系统疾病和癌症中被误导。我们的工作将确定细胞周期过渡的靶标和小分子抑制剂，这两种学术临床研究都可以用于治疗诸如髓母细胞瘤等疾病。