Our overall goal is to achieve an understanding of the molecular mechanisms regulating cell divisions. The proposed studies utilize the model organism Caenorhabditis elegans to investigate the regulatory interactions between developmental signals and the cell cycle. Our research plan proposes to identify the pathways that control cdc-14, a critical regulator of cell-cycle entry during development. cdc-14 acts together with cki-1, a member of the p27Kip1 family of cyclin-dependent kinase inhibitors, within a network that regulates cell-cycle quiescence. Our strategies apply the excellent developmental genetics of C. elegans to reveal detailed mechanisms to inhibit G1 progression by modulating cdc-14 activity. We propose three aims to identify the pathways that connect developmental signals to control of G1 progression: 1) To determine the mechanisms used to restrict cdc-14 activity to those cells in which this phosphatase specifies temporarily cell-cycle quiescence during development. We focus on two processes that direct the cell-type specification of cdc-14 activity: restricted expression and subcellular compartmentalization. These analyses utilize a series of modified cdc-14 transgenes designed to manipulate CDC-14 expression and subcellular localization and the corresponding G1 regulatory activity of such transgenes. 2) To identify additional genes that act within the cdc-14-mediated network in a reverse-genetic screen for defects in control of G1 progression. Our screen utilizes a strategy to produce visible defects in cell- cycle control, allowing for efficient and simple identification. 3) To develop a genetic hierarchy using the genes identified in the described screen. The organization of this network will be based on tests to define the genetic interactions, effect on CDC-14 expression and subcellular localization of the new genes. Together, the proposed studies will define the pathway to control cdc-14 activity during development and will provide insights into the general mechanisms used to integrate cell-cycle regulation with growth and development. The goal of this proposal is to understand the mechanisms used to control the activity of cdc-14, a gene that plays an important role to temporarily stop cells from dividing. These results may provide insights into how tumors are formed since cancers are characterized by defects in genes that control cell divisions.
|Roy, Sarah H; Tobin, David V; Memar, Nadin et al. (2014) A complex regulatory network coordinating cell cycles during C. elegans development is revealed by a genome-wide RNAi screen. G3 (Bethesda) 4:795-804|
|Tobin, David V; Saito, Richard Mako (2012) Developmental decisions: balancing genetics and the environment by C. elegans. Cell Cycle 11:1666-71|
|Roy, Sarah H; Clayton, Joseph E; Holmen, Jenna et al. (2011) Control of Cdc14 activity coordinates cell cycle and development in Caenorhabditis elegans. Mech Dev 128:317-26|
|Buck, Sarah H; Chiu, Daniel; Saito, R Mako (2009) The cyclin-dependent kinase inhibitors, cki-1 and cki-2, act in overlapping but distinct pathways to control cell cycle quiescence during C. elegans development. Cell Cycle 8:2613-20|