Regulation of Radiation Induced Cell Death in Drosophila

描述（由申请人提供）： 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哺乳动物细胞的研究，这些研究确定了模式生物如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，在分子水平上仍然知之甚少。 最近的研究表明，在没有任何p53样活性的情况下，由于果蝇中唯一的p53家族成员的突变，辐照细胞发生了强烈的凋亡，从而提供了第一个研究IR诱导的p53非依赖性凋亡的遗传模型。果蝇中p53依赖性和p53非依赖性细胞凋亡具有共同的特征，例如需要caspase活性和受损的DNA损伤检查点或DNA修复加剧。p53依赖性细胞凋亡和p53非依赖性细胞凋亡之间的关键区别在于，净E2 F活性似乎促进前者，但抑制后者。为了在分子水平上了解p53非依赖性细胞凋亡，将使用遗传学和细胞学方法的组合来识别和研究果蝇中这种细胞死亡模式所需的基因及其产物。 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的研究，它是p53非依赖性细胞凋亡是至关重要的消除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-独立的细胞凋亡在体内的多细胞背景下。鉴于果蝇和人类之间基因功能的保守性，这里提出的研究有可能帮助我们最大限度地提高人类癌症放射治疗的疗效。 公共卫生相关性： 使用电离辐射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的研究，它是p53非依赖性细胞凋亡，是至关重要的消除p53缺陷的肿瘤，这构成了大多数。这里提出的实验将导致更好地了解p53-独立的细胞凋亡，结果从辐射暴露在果蝇模型。由于果蝇和人类之间基因功能的高度保守性，我们的研究可能使我们能够最大限度地提高人类癌症的放射治疗效果。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: NARRATIVE The use of ionizing radiation 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. Experiments proposed here will lead to a better understanding of p53- independent apoptosis that results from radiation exposure in a Drosophila model. Because of excellent conservation of gene function between Drosophila and human, what we learn may allow us to maximize the efficacy of radiation therapy of human cancers.