Regulation of Radiation Induced Cell Death in Drosophila

摘要 电离辐射(IR)诱导P53依赖和非P53非依赖的细胞凋亡。 了解依赖于P53的细胞凋亡从哺乳动物的研究中受益匪浅 在模式生物中鉴定生化活动和遗传分析的细胞，如C. 线虫和果蝇确定了负责这些活动的基因。相比之下，IR- 诱导的P53非依赖性细胞凋亡缺乏遗传模型，目前仍知之甚少。 分子水平。 最近资助期的研究表明，在没有任何P53样活性的情况下， 由果蝇中唯一的p53家族成员突变而成，受辐射的细胞 经历强烈的细胞凋亡，从而提供了第一个研究IR诱导的P53- 独立的细胞凋亡。果蝇体内P53依赖和非P53依赖的细胞凋亡 共同的特征，如对caspase活性的要求和受损的恶化 DNA损伤检查站或DNA修复。P53依赖的细胞凋亡的关键区别 而P53非依赖性的细胞凋亡则是净E2F活性似乎促进了前者而抑制了前者 后者。为了在分子水平上理解P53非依赖性的细胞凋亡， 遗传学和细胞学方法将用于鉴定和研究基因及其产物。 果蝇的这种细胞死亡模式所需要的。 使用IR来根除肿瘤依赖于其诱导细胞死亡的能力。虽然P53- 依赖性细胞凋亡仍然是研究最广泛的，它是P53非依赖性的细胞凋亡 对于消除P53缺陷型肿瘤至关重要，P53缺陷型肿瘤占实体肿瘤的大多数。 拟议的实验将有助于更好地理解活体内非依赖于p53的细胞凋亡 在多细胞环境中。鉴于果蝇和果蝇之间基因功能的保守性 人类，这里提出的研究有可能帮助我们最大限度地发挥辐射的功效 人类癌症的治疗。

SUMMARY Ionizing Radiation (IR) induces p53-dependent and p53-independent apoptosis. Understanding p53-dependent apoptosis has benefited immensely from studies in mammalian cells that identified biochemical activities and genetic analysis in model organisms such as C. elegans and Drosophila that identified genes responsible for the activities. In contrast, IR- induced p53-independent apoptosis lacked a genetic model and remains poorly understood at the molecular level. Studies in recent funding period indicate that in the absence of any p53-like activity, made possible by mutations in the sole p53 family member in Drosophila, irradiated cells undergo robust apoptosis, thus providing the first genetic model to study IR-induced p53- independent apoptosis. p53-dependent and p53-independent apoptosis in Drosophila share common features such as the requirement for caspase activity and exacerbation by impaired DNA damage checkpoints or DNA repair. The key difference between p53-dependent apoptosis and p53-independent apoptosis is that net E2F activity appears to promote the former but inhibit the latter. To understand p53-independent apoptosis at the molecular level, a combination of genetic and cytological approaches will be used to identify and study genes and their products needed for this mode of cell death in Drosophila. The use of IR to eradicate tumors relies on its ability to induce cell death. Although p53- dependent apoptosis remains most widely studied, it is p53-independent apoptosis that is crucial for eliminating p53-deficient tumors, which constitute the majority of solid tumors. Experiments proposed will lead to a better understanding of p53-independent apoptosis in vivo in a multi-cellular context. Given the conservation of gene function between Drosophila and human, research proposed here has the potential to help us maximize the efficacy of radiation therapy of human cancers.