The ability of a cell to grow and divide in variable environments is contingent on its ability to sense and respond appropriately to external change. Throughout eukaryotes, mitogen activated protein kinase pathways (MAPK) are frequently used to link external changes to downstream cellular responses, which necessarily includes cell cycle regulation. In this proposal, we focus on control of the cell cycle by the pheromone-induced MAPK pathway in budding yeast. Information about pheromone concentration is integrated in G1 phase, prior to the 'Start'of the cell cycle. Whereas pre-Start early G1 cells arrest their cell cycle directly when exposed to mating pheromone, post-Start late G1 cells are unaffected until the subsequent cycle. Due to our extensive molecular knowledge of both the genes involved and their biochemical interactions, Start serves as a model for cell cycle commitment in eukaryotes. Here, we aim to apply dynamical systems theory to attain a comprehensive understanding of checkpoint control and advance our understanding of genetic circuits governing cellular transitions. More specifically, we aim to understand how genetic circuits are implemented to generate mutually exclusive cell fates, and, once a particular fate is selected, how large transcriptional programs are seamlessly actuated to effect cellular transitions. Across yeasts, the core function of the genetic control network at the interface between the pheromone-induced MAPK pathway and the cell cycle, i.e., to separate mating from mitosis, remains unchanged. However, there has been dramatic evolution of the components of both the cell cycle and MAPK pathways. By initiating a parallel set of experiments using the fission yeast model, we aim to investigate the hypothesis that evolution has acted to conserve the dynamical systems properties rather than the individual parts of the regulatory network. Our experimental program is comprised of both single-cell microscopy and novel bioinformatic algorithms to analyze genome-wide datasets. Notably, we employ a microfluidic platform that allows time-lapse phase and fluorescence imaging during rapid exposure to mating pheromone. Our algorithms and analysis will be applicable to a wide range of systems.
Genes involved in the core processes of cell cycle control are frequently mutated in cancers. Since cell cycle regulation is highly conserved across eukaryotes, the concepts and techniques developed in the proposed research are likely to provide a broader and deeper understanding of the human system and to give insight into oncogenesis.
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