Apoptosis in Drosophila-From Reaper to Death

描述（由申请人提供）：细胞凋亡是遗传控制的 在发育和体内平衡过程中不需要的或受损的细胞的死亡。在 近年来，遗传学和生物化学方法的结合已经被 用于识别几个分子家族，这些分子家族的作用是促进或 防止细胞凋亡。尽管我们在基本知识方面取得了这些进展， 关于细胞凋亡的机制，我们仍然对这个过程知之甚少。 在正常的开发过程中被调节和执行。我们的长期目标 研究是利用强大的遗传学机制来研究发育性细胞凋亡。 和分子技术。这些研究将提供一个 为理解细胞凋亡如何在疾病中被错误调节奠定了基础， 神经退化和癌症。收割者（RPR），严峻和隐藏的基因作为 果蝇胚胎中细胞凋亡的中心启动子。在所有人都缺席的情况下 三个基因胚胎凋亡被阻断。这些基因中的每一个都诱导 当异位表达时半胱天冬酶依赖性凋亡。RPR的当前模型 和HID活性预测细胞凋亡是由物理相互作用启动的 Rpr、Grim和Hid与凋亡抑制剂DIAP 1的关系。我们的初步 这种模式过于简单化。我们建议使用 结合遗传和生化策略来测试替代模型 用于Rpr和Hid与DIAPI的交互。差异表达模式 grim和hid的表达表明它们在调节 发育性凋亡为了检查rpr的需求，我们生成了 一种去除rpr g的突变体。我们对这一现象的初步描述 突变体揭示了在程序性死亡中对该基因的独特需求 神经母细胞因为成神经细胞代表了一个特定的细胞群 以rpr依赖的方式进行细胞凋亡，我们可以集中我们的 研究这些细胞中凋亡程序的调节。不 只有RPR、HID和GRIM是细胞凋亡启动所必需的。 在发育过程中，它们也是高水平凋亡所必需的， 胚胎中的DNA损伤虽然果蝇p53（Dmp53）直接调节 rpr表达，我们的数据表明，单独缺失rpr并不能阻断 DMP53诱导的细胞凋亡。在rpr突变的背景下，我们将测试其他基因 他们在这起死亡事件中的作用，并确定DMP53的替代目标。这 这项工作将提高我们对p53如何诱导细胞凋亡的理解。

DESCRIPTION (provided by applicant): Apoptosis is the genetically controlled death of unwanted or damaged cells during development and homeostasis. In recent years, a combination of genetic and biochemical approaches have been used to identify several families of molecules which act to facilitate or prevent apoptosis. Despite these advances in our knowledge of the basic machinery of apoptosis, we still know relatively little about how this process is regulated and executed during normal development. The long term goal of our research is to investigate developmental apoptosis using the powerful genetic and molecular techniques available in Drosophila. These studies will provide a foundation for understanding how apoptosis is misregulated in diseases such as neurodegeneration and cancer. The reaper (rpr), grim and hid genes act as central initiators of apoptosis in the Drosophila embryo. In the absence of all three genes embryonic apoptosis is blocked. Each of these genes induces caspase-dependent apoptosis when ectopically expressed. Current models for rpr and hid activity predict that apoptosis is initiated by physical interactions between Rpr, Grim and Hid with the apoptosis inhibitor DIAP1. Our preliminary data suggests-that this model is oversimplified. We propose to use a combination of genetic and biochemical strategies to test alternative models for Rpr and Hid interactions with DIAPI. The differential expression patterns of rpr, grim and hid suggest that they have unique functions in regulating developmental apoptosis. To examine the requirement for rpr, we have generated a mutant that removes the rpr g. Our preliminary characterization of this mutant has revealed a unique requirement for this gene in the programmed death of neuroblasts. Because the neuroblasts represent a defined population of cells that undergo apoptosis in a rpr-dependent manner, we can focus our investigations on the regulation of the apoptotic program in these cells. Not only are rpr, hid and grim essential for the initiation of apoptosis during development, they also are required for high levels of apoptosis in response to DNA damage in the embryo. Although Drosophila p53 (Dmp53) directly regulates rpr expression, our data indicate that deletion of rpr alone does not block Dmp53-induced apoptosis. In the rpr mutant background we will test other genes for their role in this death, and identify alternative targets of Dmp53. This work will improve our understanding of how p53 induces apoptosis.