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Regulation of Radiation Induced Cell Death in Drosophila

果蝇辐射诱导细胞死亡的调控

基本信息

批准号：
8327206
负责人：
Tin Tin Su
金额：
$ 30.79万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-08-31
项目状态：
已结题

项目摘要

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.

概括电离辐射 (IR) 诱导 p53 依赖性和 p53 非依赖性细胞凋亡。对 p53 依赖性细胞凋亡的理解极大地受益于对哺乳动物的研究识别模式生物（如 C. 线虫和果蝇鉴定出负责这些活动的基因。相反，IR- 诱导的不依赖于 p53 的细胞凋亡缺乏遗传模型，目前仍知之甚少。分子水平。最近资助期间的研究表明，在没有任何 p53 样活性的情况下，果蝇中唯一的 p53 家族成员的突变使之成为可能，辐射细胞经历强烈的细胞凋亡，从而提供第一个研究 IR 诱导的 p53- 的遗传模型独立凋亡。果蝇中p53依赖性和p53非依赖性细胞凋亡的比例共同特征，例如对 caspase 活性的需求以及受损导致的恶化 DNA 损伤检查点或 DNA 修复。 p53依赖性细胞凋亡之间的主要区别和 p53 独立的细胞凋亡是净 E2F 活性似乎促进前者但抑制后者。为了在分子水平上了解 p53 独立的细胞凋亡，结合遗传和细胞学方法将用于识别和研究基因及其产物果蝇的这种细胞死亡模式是必需的。使用红外线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，p53 独立细胞凋亡是对于消除 p53 缺陷型肿瘤至关重要，p53 缺陷型肿瘤占实体瘤的大多数。提出的实验将有助于更好地了解体内 p53 独立细胞凋亡在多细胞环境中。鉴于果蝇和人类，这里提出的研究有可能帮助我们最大限度地发挥辐射功效人类癌症的治疗。