Cell Cycle Control in Early Drosophila Development

描述（由申请人提供）：在发育过程中，多细胞生物必须与细胞增殖协调分化，并且细胞周期被修改以实现特定的发育目标。两种不同细胞周期的调控正在以果蝇为模型进行研究：减数分裂，一种修改的细胞周期，其中两轮染色体分离允许产生单倍体配子，以及一种用于早期胚胎发生的快速细胞周期。减数分裂细胞周期受发育控制，通过减数分裂与卵母细胞分化和受精协调进展。了解这些周期的控制回路将有助于了解人类不孕症的原因，而确定的调节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存在现成的联系。在果蝇中发现的细胞周期控制基因通常具有在人类中起重要作用的同源物。一种蛋白激酶复合物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CDK1激酶亚基结合时，促进有丝分裂并抑制DNA复制。PAN GU调控Cyclin B翻译的机制将被明确，阐明翻译控制在触发有丝分裂发生中的作用。在先前的资助期内，在控制减数分裂细胞周期方面有缺陷的突变体被恢复。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，蛋白质靶点将被确定。这将揭示蛋白质降解在减数分裂染色体分离中的作用，并导致鉴定对减数分裂至关重要的蛋白质。在受精时完成减数分裂和重新开始细胞周期所必需的其他基因的蛋白质产物将被分离出来。

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.