Probing Complexity of UV Induced Apoptosis in Drosophila

探讨果蝇紫外线诱导细胞凋亡的复杂性

• 批准号: 6928573
• 负责人: Lei Zhou
• 金额: $ 24.19万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928573
• 关键词: DNA damage; Drosophilidae; apoptosis; arthropod genetics; biological signal transduction; developmental genetics; gene environment interaction; gene expression; genetic regulation; genetic regulatory element; invertebrate embryology; radiation genetics; transcription factor; ultraviolet radiation

DESCRIPTION (provided by applicant): Probing the complexity of UV induced apoptosis in Drosophila: Apoptosis is an evolutionarily conserved process that has been implicated in a variety of diseases, including cancer and neurodegenerative diseases. Regulation of apoptosis is under the control of a complex network of genes (proteins). Our preliminary data showed that UV induced apoptosis in Drosophila embryo can be mediated by different cell death regulatory genes. More interestingly, the cellular context (differentiation status) of the irradiated cell determines which cell death regulatory gene is activated to induce cell death upon UV irradiation, i.e. When embryos in differentiating stage were irradiated with UV, the reaper gene is induced by a DNA damage -dependent mechanism that involves Drosophila homologue of Ataxia Telangiectasia Mutated, mei-41 (and very likely dP53 as well). However, when embryos prior to differentiating stage were irradiated, the hac-1 (Homologue of Apaf-1 and Ced-4) gene is induced instead of reaper. The induction of hac-1 expression is required for UV induced apoptosis at this developmental stage. But in contrast to UV induction of reaper, UV induction of hac-1 appears to be independent of nuclear DNA damage and was not affected by mei-41 mutation (mei-41 [D5]). It has long been noticed that UV induced cell death can be mediated by DNA damage -dependent and -independent mechanisms. However, it remains unclear as to how are the mechanisms deployed and coordinated to mediate UV induced apoptosis. The aforementioned findings indicate that Drosophila embryo provides an excellent model for systematic analysis of the complexity of UV -induced cell death. The focus of this proposal is to characterize the molecular mechanism underlying UV induced hac- 1 expression and apoptosis in early stage embryos. In addition, we will apply genomic approaches to gain comprehensive understanding of UV -induced genomic response and apoptosis. The goal of this proposal is to elucidate in depth how different cell death regulatory pathways may be deployed to mediate genotoxic stimuli -induced cell death. The information provided by these investigations will contribute to our comprehensive understanding of cell death regulation and skin carcinogenesis. Molecular mechanisms uncovered through this project should provide insights for identifying alternative therapeutic targets, especially for cancers that are resistant to DNA-damage agents.

描述（由申请人提供）：探测果蝇中紫外线诱导的凋亡的复杂性：凋亡是一种进化保守的过程，与多种疾病有关，包括癌症和神经退行性疾病。凋亡的调节在复杂的基因网络（蛋白质）的控制之下。我们的初步数据表明，紫外线诱导的果蝇胚胎凋亡可以通过不同的细胞死亡调节基因介导。更有趣的是，受辐照细胞的细胞环境（分化状态）决定了哪种细胞死亡调节基因被激活在紫外线照射时诱导细胞死亡，即，当在分化阶段的胚胎被辐照的胚胎时，receper基因被receper基因诱导，而DNA损伤的机制可能会导致依赖于Drosophila telosophila telosiaia teleciaia telasax telecy telangiaia telangiaia telangiaia telangiaia telangiaia telangiaia telangiaia（telangiaia）（ DP53也）。但是，当辐照分化阶段之前的胚胎时，诱导HAC-1（APAF-1和CED-4的同源物）而不是收割机。在此发育阶段，紫外线诱导的凋亡需要HAC-1表达的诱导。但是，与收割机的紫外线诱导相反，HAC-1的紫外线诱导似乎与核DNA损伤无关，并且不受MEI-41突变的影响（MEI-41 [D5]）。长期以来，已经注意到，紫外线诱导的细胞死亡可以由DNA损伤依赖性和非依赖性机制介导。但是，尚不清楚如何在介导紫外线诱导的凋亡中部署和协调的机制。上述发现表明，果蝇胚胎为系统分析紫外线诱导的细胞死亡提供了出色的模型。该建议的重点是表征紫外线诱导的HAC-1表达和早期胚胎凋亡的分子机制。此外，我们将采用基因组方法来全面了解紫外线诱导的基因组反应和凋亡。该提案的目的是深入阐明如何部署不同的细胞死亡调节途径来介导遗传毒性刺激诱导的细胞死亡。这些研究提供的信息将有助于我们对细胞死亡调节和皮肤致癌作用的全面理解。通过该项目发现的分子机制应提供识别替代性治疗靶标的见解，特别是对于耐DNA破坏药物的癌症。