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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.

总结电离辐射（IR）诱导p53依赖性和p53非依赖性细胞凋亡。了解p53依赖的细胞凋亡极大地受益于哺乳动物中的研究。在模式生物如C. elegans和Drosophila发现了负责这些活动的基因。相反，IR- 诱导的p53非依赖性细胞凋亡缺乏遗传模型，分子水平。最近的研究表明，在没有任何p53样活性的情况下，通过果蝇中唯一的p53家族成员的突变，经历了强大的凋亡，从而提供了第一个遗传模型来研究IR诱导的p53- 独立凋亡。果蝇中p53依赖性和非p53依赖性细胞凋亡的研究共同的特点，如对半胱天冬酶活性的要求和受损的恶化， DNA损伤检查点或DNA修复。p53依赖性细胞凋亡而p53非依赖性细胞凋亡是E2 F活性促进前者，但抑制p53非依赖性细胞凋亡。后者为了在分子水平上理解p53非依赖性细胞凋亡，将采用遗传学和细胞学方法来鉴定和研究基因及其产物果蝇这种细胞死亡模式所需要的。使用IR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最广泛研究的，它是p53非依赖性细胞凋亡，对于消除p53缺陷型肿瘤至关重要，p53缺陷型肿瘤构成了大多数实体瘤。提出的实验将导致更好地了解p53非依赖性细胞凋亡在体内在多细胞环境中。考虑到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提高辐射的功效治疗人类癌症。