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

描述（由申请人提供）：致癌作用是由癌基因和肿瘤抑制基因的失调引起的，这允许过度的细胞增殖和组织生长。Dlc 1（动力蛋白轻链1）基因编码一种非常保守的蛋白质，可以促进培养细胞中的癌表型，并在人类癌症中失调。我们的目标是使用果蝇作为模型系统来阐明Dlc 1影响癌症的细胞生物学过程的分子途径，包括细胞分裂，生长和存活。Dlc 1蛋白最初被描述为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，Dlc 1在细胞中发挥着各种动力蛋白独立的作用，作为一个“二聚化枢纽”，以促进形成更高级的蛋白质复合物。使用果蝇作为模型系统，我们已经确定了一个以前未描述的表型，即“敲低”Dlc 1蛋白与RNAi转基因减少器官大小。这种表型提供了一个独特的机会，从遗传学角度剖析Dlc 1的生长调节功能。此外，初步数据表明dMyc（人癌基因c-Myc的直向同源物）和DIAP 1（关键抗凋亡蛋白）的水平在Dlc 1缺陷细胞中降低，从而将Dlc 1与在人细胞生长和存活中起保守作用的蛋白质连接。 细胞也是。Aim 1研究将描述Dlc 1缺失对发育中上皮细胞生长、分裂和死亡的影响。Aim 2将检测Dlc 1敲低后关键保守生长调节途径的活性，特别关注Hippo/Mst 2途径。与此同时，我们将进行一个基因组范围内的屏幕Dlc 1缺陷生长表型的显性修饰符。这些研究数据的整合将有助于确定Dlc 1调节果蝇器官大小的机制，也许也可以在人类细胞中进行。这些信息对于了解Dlc 1对人类致癌作用的贡献至关重要，并可能为Dlc 1失调的癌症开发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.