Poster abstracts
Poster number 10 submitted by Marcos Corchado
LPR-3 as a cell non-autonomous regulator of activated LET-60/RAS in C. elegans
Marcos Corchado (Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA), Komal Rambani (Department of Biomedical Sciences, Ohio State University, Columbus, Ohio 43210, USA), Gustavo Leone (Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA), Helen M. Chamberlin (Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA)
Abstract:
Extracellular signals from the stroma are required for the maintenance and progression of tumors. However, identifying such factors is particularly challenging due to the complexity of stromal cell types in mammals. In a recent collaboration, our lab co-developed a simple model for the tumor microenvironment based on C. elegans vulva development. Here, the mesoderm serves as a model for the stroma, while the epithelial vulva precursor cells (VPCs) model the tumor. Key to this system is a genetic modification restricting RNAi response to the mesoderm. Additionally, a gain-of-function mutation, let-60(gf), promoted increased cell division of VPCs, resulting in multi-vulva (MUV) animals with visible ventral protrusions. In humans, a hyperactive allele of Ras, the let-60 ortholog, leads to deregulation of the Ras-MAPK pathway, resulting in increased cell cycle progression and cancer. Using this system, a genome-wide RNAi screen was performed to identify genes that, upon knockdown, act as cell non-autonomous suppressors of let-60(gf). Surprisingly, only one gene encoded a secreted protein –lipocalin-related 3 (lpr-3). Most lipocalins transport hydrophobic ligands and initiate signaling cascades by binding to specific membrane receptors. The following work presents proposed research to elucidate the mechanism of LPR-3 and test the hypothesis that LPR-3 is secreted and binds to a receptor to promote activated let-60 signaling. In Aim 1 I will characterize the expression profile and conserved lipocalin functions of lpr-3. Aim 2 will test the hypothesis that LPR-3 binds to a receptor in the VPC membrane. Finally, Aim 3 focuses on identifying the endogenous LPR-3 ligand.
Keywords: lipocalins, Ras, C elegans