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.
The applicants have discovered a growth regulatory role for a gene in fruit flies (called Dlc1) and have noted its impact on other cancer-related genes. Understanding the regulation of growth genes and the mechanisms of their action is vital to generating innovative cancer therapies. Our work will contribute to the understanding of Dlc1's role in developmental growth and human diseases such as cancer.
| Barron, Daniel A; Moberg, Kenneth (2016) Inverse regulation of two classic Hippo pathway target genes in Drosophila by the dimerization hub protein Ctp. Sci Rep 6:22726 |
