DEVELOPMENTAL PROGRAMS OF CELL CYCLE CONTROL

细胞周期控制的发育程序

• 批准号: 2444632
• 负责人: PATRICK H O'FARRELL
• 金额: $ 26.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2444632
• 关键词: DNA directed RNA polymerase; DNA replication; DNA replication origin; Drosophilidae; cell cycle; cell growth regulation; cellular polarity; cyclins; developmental genetics; egg /ovum; embryogenesis; fluorescence microscopy; genetic regulation; genetic transcription; mutant; phosphorylation; protein degradation; protein kinase; synthetic nucleic acid

The precise patterns of embryonic cell division contribute to normal morphogenesis and reflect tight control of cell proliferation in metazoans. Identification of the mechanisms of this control should illuminate aspects of embryonic patterning and of diseases resulting from defects in the control of cell proliferation. Cell cycle regulators and the developmental programs that influence their activity are widely conserved. However, development does not simply impose controls on a standard cell cycle. It changes the very nature of the cycle, deleting and adding steps by changing the levels of fundamental cell cycle components. Drosophila provides a powerful model system for analyses of these developmental controls: in addition to genetic, molecular and developmental tools, many characterized cell cycle regulators are available in this organism. Cycles 1-7 forgo all familiar controls. Only exit from mitosis seems regulated, perhaps by cytoskeletal influences on cyclin B degradation. The importance of cyclin degradation will be tested by introduction of non-destructible mutants of cyclin, and cyclin stability will be examined in mutants defective in arrest at the first mitosis. During cycles 1-16, progress to S phase is limited only by a requirement to pass through mitosis. The DNA is thought to gain the license to replicate once each time it passes through mitosis. We will test the roles of candidate licensing factor genes cloned by homology to yeast replication genes. Progress to mitosis is usually blocked if DNA synthesis is arrested. This S phase checkpoint control involves inhibitory phosphorylation of Cdc2, and becomes operative only at cycle 14 when this inhibitory phosphorylation first occurs. We will examine regulation of a recently cloned kinase that is apparently responsible for this inhibitory phosphorylation. Rapid cell cycling inhibits transcription in early embryos, and cycle lengthening appears to be a key regulator of transcription. We will test whether the mitotic Cdc2 kinase directly inhibits transcription by phosphorylating RNA polymerase, and whether passage of a replication fork interferes with ongoing transcription. In cycle 14, another feature of cell cycle control becomes evident: the orientation of cell division planes is regulated. We will identify genes responsible for re-orienting division planes in stereotyped patterns.

胚胎细胞分裂的精确模式有助于正常 形态发生并反映对细胞增殖的严格控制 后生动物。识别该控制的机制应 阐明胚胎图案的方面和疾病的疾病 控制细胞增殖的缺陷。 细胞周期调节剂和 影响其活动的发展计划广泛 保守。但是，发展并不只是对 标准细胞周期。它改变了周期，删除和 通过更改基本细胞周期成分的水平来添加步骤。 果蝇提供了一个强大的模型系统，用于分析这些系统 发展控制：除了遗传，分子和 发展工具，许多表征的细胞周期调节器是 可在此生物体中使用。循环1-7放弃了所有熟悉的控件。仅有的 从有丝分裂的退出似乎受到了细胞骨架影响的调节 细胞周期蛋白B降解。将测试细胞周期蛋白降解的重要性 通过引入细胞周期蛋白和细胞周期蛋白的不破坏性突变体 稳定性将在第一次被逮捕的突变体中检查 有丝分裂。在循环1-16期间，对S相的进展仅受A的限制 经过有丝分裂的要求。 DNA被认为获得了 每次通过有丝分裂复制一次的许可。我们将 测试同源性克隆的候选许可因子基因的作用 酵母复制基因。如果DNA，通常会阻止有丝分裂的进展 合成被捕。该相位检查点控制涉及抑制 Cdc2的磷酸化，并且仅在14周期才能起作用 抑制性磷酸化首先发生。我们将检查 最近克隆的激酶显然负责这种抑制作用 磷酸化。 快速细胞循环抑制早期转录 胚胎和循环延长似乎是 转录。我们将测试有丝分裂CDC2激酶是否直接 通过磷酸化RNA聚合酶抑制转录，以及是否是否 复制叉的通过会干扰持续的转录。在 周期14，细胞周期控制的另一个特征变得明显： 调节细胞分裂平面的方向。我们将识别基因 负责以刻板印象的方式重新定位划分平面。