Cell Cycle Control in Early Drosophila Development

描述(申请人提供)：在发育过程中，多细胞生物必须协调分化和细胞增殖，并修改细胞周期以实现特定的发育目标。目前正在以果蝇为模型研究两种不同细胞周期的调节：减数分裂，一种改良的细胞周期，其中两轮染色体分离允许产生单倍体配子；另一种是早期胚胎发育中使用的快速细胞周期。减数分裂细胞周期受到发育控制，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深入了解人类不孕不育的原因，而已识别的调控基因可能对预防癌症很重要。果蝇是发现基因功能的理想模式生物，因为突变恢复和蛋白质鉴定之间有很好的联系。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同源基因。一种蛋白激酶复合体，盘古，通过控制Cyclin B的翻译来驱动胚胎周期，Cyclin B是一种关键蛋白质，当与CDK1激酶亚单位复合时，促进有丝分裂并抑制DNA复制。将确定盘古调节Cyclin B翻译的机制，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，恢复了在控制减数分裂细胞周期方面有缺陷的突变体。其中两种受影响的蛋白质似乎是泛素介导的蛋白质降解所必需的。它们的作用机制将被确定，蛋白质靶标将被确定。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。完成减数分裂和在受精时重新启动细胞周期所需的其他基因的蛋白质产物将被分离。

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.