The Anaphase Promoting Complex and Cell Cycle Exit

描述(由申请人提供)：了解神经发生取决于阐明细胞周期退出。所有细胞周期转变的一个基本特征是不可逆转性。一旦承诺进入特定的细胞周期阶段，就不可能返回到前一个阶段。这在一定程度上是由于泛素介导的蛋白分解途径以蛋白酶体降解的底物为目标。泛素介导的蛋白分解途径包含调节降解事件的时间和保真度的E1、E2和E3酶。最重要的E3酶之一是一个多亚基复合体，称为后期促进复合体，简称APC。APC控制着中期到后期的过渡和有丝分裂的退出。APC在细胞周期退出和神经元前体分化过程中也是活跃的。APC降解泛素连接酶组分Skp2，使p27kip1水平上升，从而诱导细胞周期退出。本研究的总体目标是验证这一假说，即在发育中的神经系统中，细胞周期退出需要由泛素连接酶-后期促进复合体(APC)控制的泛素介导的蛋白分解。 与公共健康相关：我们正在研究控制神经前体细胞增殖的机制。在神经系统疾病和癌症中，这些机制经常被错误地调节。我们的工作将确定细胞周期转变的靶点和小分子抑制剂，可用于治疗髓母细胞瘤等疾病的学术临床研究。

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.