Dynein light chain 1 (Dlc1) regulates growth in Drosophila melanogaster

描述(由申请人提供)：癌基因和肿瘤抑制基因的解除调控导致细胞过度增殖和组织生长，从而加剧了癌症的发生。Dlc1(动力蛋白轻链1)基因编码一种非常保守的蛋白质，可以促进培养细胞的癌变表型，在人类癌症中是非调控的。我们的目标是以果蝇为模型系统，阐明Dlc1影响肿瘤细胞生物学过程的分子途径(S)，包括细胞分裂、生长和存活。Dlc1蛋白最初被描述为其在动力蛋白运动复合体中的辅助作用。现在越来越清楚的是，Dlc1在细胞中扮演着一种不依赖于动力蛋白的角色，它扮演着促进高阶蛋白质复合体形成的‘二聚化中心’的角色。使用果蝇作为一个模型系统，我们已经确定了一种以前未描述的表型，即通过RNAi转基因‘击倒’Dlc1蛋白减小器官大小。这种表型为从基因上剖析Dlc1的生长调节功能提供了一个独特的机会。此外，初步数据表明，在缺乏Dlc1的细胞中，dMyc(人类癌基因c-Myc的同源基因)和DIAP1(关键的抗凋亡蛋白)的水平降低，从而将Dlc1与在人类细胞生长和生存中发挥保守作用的蛋白质联系起来 细胞也是如此。对Aim1的研究将表征Dlc1缺失对发育中的上皮细胞生长、分裂和死亡的影响。AIM2，将分析Dlc1基因敲除后关键保守的生长调节途径的活性，特别是HIPPO/Mst2途径。同时，我们将在全基因组范围内筛选Dlc1缺陷生长表型的显性修饰基因。整合这些研究的数据将有助于确定Dlc1调节果蝇器官大小的机制，可能也包括在人类细胞中。这些信息对于理解Dlc1在人类癌症发生中的作用至关重要，并可能为开发针对Dlc1基因缺失的癌症的靶向治疗提供新的机会。

DESCRIPTION (provided by applicant): Carcinogenesis is fueled by the deregulation of oncogenes and tumor suppressor genes, which allows for excessive cell proliferation and tissue growth. The Dlc1 (dynein light chain 1) gene encodes a very well conserved protein that can promote cancerous phenotypes in cultured cells and is deregulated in human cancers. Our goal is to use Drosophila as a model system to elucidate the molecular pathway(s) through which Dlc1 influences cell biological process that underlie cancer, including cell division, growth and survival. The Dlc1 protein was originally described for its accessory role in dynein motor complexes. It is now becoming clear that Dlc1 plays a variety of dynein-independent roles in the cell by acting as a 'dimerization hub' to promote the formation of higher-order protein complexes. Using Drosophila as a model system, we have identified a previously undescribed phenotype whereby 'knocking down' Dlc1 protein with an RNAi transgene reduces organ size. This phenotype offers a unique opportunity to genetically dissect the growth regulatory function of Dlc1. Furthermore, preliminary data indicate that the levels of dMyc (the ortholog of the human oncogene c-Myc) and DIAP1 (a key anti-apoptotic protein) are reduced in Dlc1 deficient cells, thus linking Dlc1 to proteins that play conserved roles in cell growth and survival in human cells as well. Studies in Aim1 will characterize the effect of Dlc1 loss on cell growth, division, and death in a developing epithelium. Aim2, will assay the activity of key conserved growth-regulatory pathways following Dlc1 knockdown, with a particular focus on the Hippo/Mst2 pathway. In parallel, we will perform a genome-wide screen for dominant modifiers of a Dlc1-deficient growth phenotype. The integration of data from these studies will help identify the mechanism through which Dlc1 regulates organ size in flies, and perhaps in human cells as well. Such information is vital to understanding the contribution of Dlc1 to human carcinogenesis and may provide new opportunities to develop targeted therapies for cancers with deregulated Dlc1.