Cell-cycle-dependent cell polarity control

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Polarized cells in retain their shape in every cell cycle and this is essential to their proper function. Anomalies in polarized cell shape can result in cancer, metabolic disorders, and loss of tissue integrity. Here, we will investigate a long-standing question of how cells consistently regain their polarity after each round of division. This investigation will be conducted using the fission yeast, Schizosaccharomyces pombe model system that provides many well characterized genetic tools to manipulate conserved proteins that influence cell shape following division. Cdc42 is the major regulator of polarized growth. In fission yeast, cells halt polarized Cdc42 activation and consequent growth at the cell ends during mitosis. After completion of division, these cell ends resume Cdc42 activation and cell growth. After division, Cdc42 activation and polarized growth always resumes in a monopolar manner from the old end that pre-exists from the previous generation. The cell transitions to bipolar growth when Cdc42 activation also resumes at the newly formed cell end in the G2 phase of the cell cycle. Our preliminary data indicate that resumption of Cdc42 activation at the old end after division and transition to bipolar activation in G2 are cell cycle dependent. Our central hypothesis is that Cdc42 is differentially regulated at the cell ends by distinct cell-cycle-dependent cues to establish the cell polarization pattern. We will test this hypothesis by pursuing the following specific aims, [1] Determine how Cdc42 activation resumes at the cell ends in the G1/S phase; [2] Elucidate how a memory of growth from the previous cell cycle enables the pre-existing old end to initiate Cdc42 activation first; [3] Explain how the transition from monopolar to bipolar growth occur in G2 phase. With this project we expect to mechanistically understand how Cdc42 activation and associated growth patterns are modulated in different cell cycle stages. We will examine how signals from one cell cycle inform the growth pattern in the next generation. This will provide much needed insights into the principles that preserve polarized cell shape in complex systems. Due to the conserved nature of the proteins involved in this investigation, we expect that our findings will be relevant cell shape control in higher eukaryotes and provide potential therapeutic or diagnostic targets for diseases such as cancer.