Cell Cycle Control in Early Drosophila Development

描述（由申请人提供）：在发育过程中，多细胞生物必须协调分化与细胞增殖，并修改细胞周期以实现特定的发育目标。两个不同的细胞周期的调节正在研究使用果蝇作为模型：减数分裂，一个修改的细胞周期，其中两轮染色体分离允许产生单倍体配子，和早期胚胎发生过程中使用的快速细胞周期。减数分裂细胞周期受发育控制，以协调减数分裂与卵母细胞分化和受精的进程。了解这些周期的控制电路将有助于了解人类不育的原因，并且所确定的调控基因可能在预防癌症方面很重要。果蝇是发现基因功能的理想模式生物，因为突变体恢复和蛋白质鉴定之间有着现成的联系。在果蝇中发现的细胞周期控制基因通常具有在人类中发挥重要作用的直系同源物。蛋白激酶复合物PAN GU通过控制细胞周期蛋白B的翻译来驱动胚胎周期，细胞周期蛋白B是一种关键蛋白，当与CDK 1激酶亚基复合时，促进有丝分裂并抑制DNA复制。PAN GU调节细胞周期蛋白B翻译的机制将被定义，阐明翻译控制在触发有丝分裂开始中的作用。在前一个资助期内，回收了控制减数分裂细胞周期有缺陷的突变体。两个受影响的蛋白质似乎是必要的泛素介导的蛋白质降解。将确定其作用机制并确定蛋白质靶点。这将揭示蛋白质降解在减数分裂染色体分离中的作用，并导致对减数分裂至关重要的蛋白质的鉴定。将分离完成减数分裂和受精时细胞周期重新开始所必需的其他基因的蛋白质产物。

DESCRIPTION (provided by applicant): During development multicellular organisms must coordinate differentiation with cell proliferation, and the cell cycle is modified to achieve particular developmental goals. The regulation of two variant cell cycles is being investigated using Drosophila as a model: meiosis, a modified cell cycle in which two rounds of chromosome segregation permit the production of haploid gametes, and a rapid cell cycle used during early embryogenesis. The meiotic cell cycle is subject to developmental control to coordinate progression through meiosis with oocyte differentiation and fertilization. Understanding the control circuitry for these cycles will provide insights into causes of human infertility, and the regulatory genes identified are likely to be important in preventing cancer. Drosophila is an ideal model organism for the discovery of gene function because of the ready link between mutant recovery and protein identification. Cell cycle control genes identified in Drosophila most often have orthologs that play essential roles in humans. A protein kinase complex, PAN GU, drives the embryonic cycles by controlling translation of Cyclin B, a key protein that when complexed with the CDK1 kinase subunit promotes mitosis and inhibits DNA replication. The mechanism by which PAN GU regulates Cyclin B translation will be defined, elucidating the role of translational control in triggering the onset of mitosis. In the previous funding period mutants defective in controlling the meiotic cell cycle were recovered. Two of the affected proteins appear to be necessary for ubiquitin-mediated protein degradation. Their mechanisms of action will be determined and protein targets identified. This will reveal the role of protein degradation in meiotic chromosome segregation and lead to the identification of proteins critical for meiosis. The protein products of other genes necessary for the completion of meiosis and the restart of the cell cycle at fertilization will be isolated.