Probing Complexity of UV Induced Apoptosis in Drosophila

描述(申请人提供)：探索紫外线诱导果蝇细胞凋亡的复杂性：细胞凋亡是一种进化上保守的过程，与多种疾病有关，包括癌症和神经退行性疾病。细胞凋亡的调控是由复杂的基因(蛋白质)网络控制的。我们的初步数据表明，紫外线诱导果蝇胚胎细胞凋亡可能是由不同的细胞死亡调控基因介导的。更有趣的是，受照射细胞的细胞环境(分化状态)决定了哪个细胞死亡调控基因在紫外线照射下被激活来诱导细胞死亡，即当处于分化期的胚胎受到紫外线照射时，收割者基因是由一种依赖DNA损伤的机制诱导的，该机制涉及到突变的毛细血管扩张性共济失调的果蝇同源物mei-41(很可能也包括dp53)。然而，当照射分化前的胚胎时，诱导的是HAC-1(APAF-1和Ced-4的同源物)基因，而不是死亡者。在这一发育阶段，紫外线诱导的细胞凋亡需要诱导HAC-1的表达。但与REPAR的紫外线诱导相反，HAC-1的紫外线诱导似乎独立于核DNA损伤，也不受mei-41突变(mei-41[D5])的影响。长期以来，人们注意到紫外线诱导的细胞死亡可以通过DNA损伤依赖和非依赖的机制来介导。然而，目前还不清楚这些机制是如何部署和协调来介导紫外线诱导的细胞凋亡的。上述结果表明，果蝇胚胎为系统分析紫外线诱导细胞死亡的复杂性提供了一个很好的模型。本研究的重点是研究紫外线诱导早期胚胎HAC-1表达和细胞凋亡的分子机制。此外，我们还将应用基因组学方法，全面了解紫外线诱导的基因组反应和细胞凋亡。这项提议的目的是深入阐明不同的细胞死亡调控途径如何被部署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全面了解细胞死亡调控和皮肤癌的发生。通过该项目发现的分子机制应该为确定替代治疗靶点提供洞察力，特别是对于对DNA损伤剂具有抗药性的癌症。

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.