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

描述（由申请人提供）：癌变是由癌基因和肿瘤抑制基因的解除管制推动的，这允许过度的细胞增殖和组织生长。dcl1（动力蛋白轻链1）基因编码一种非常保守的蛋白质，该蛋白质可以在培养细胞中促进癌症表型，并且在人类癌症中不受调节。我们的目标是利用果蝇作为模型系统来阐明dcl1影响癌症细胞生物学过程的分子途径，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物中的辅助作用。现在越来越清楚的是，dcl1在细胞中发挥着多种与动力蛋白无关的作用，作为“二聚化中心”促进高阶蛋白质复合物的形成。使用果蝇作为模型系统，我们已经确定了一种以前描述过的表型，即用RNAi转基因“敲除”dcl1蛋白会减少器官大小。这种表型提供了一个独特的机会来遗传剖析dcl1的生长调节功能。此外，初步数据表明，dMyc（人类癌基因c-Myc的同源物）和DIAP1（一种关键的抗凋亡蛋白）的水平在Dlc1缺陷细胞中降低，从而将Dlc1与在人类细胞生长和存活中发挥保守作用的蛋白联系起来

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.