Determine how protein synthesis is regulated during cell growth and division

Ohio State University, Columbus OH

Investigators

Abstract

PROJECT SUMMARY (See instructions): Cell growth and division are the essential processes for tissue homeostasis, regeneration, and cancer development. Therefore, the study of cell growth regulation is important for understanding impaired tissue regeneration and tumorigenesis. Cell growth and cell division are coordinated via mutual regulation, and these two processes together determine a fundamental cellular property, the cell size. The molecular mechanisms underlying the linkages between these processes are largely unknown. Cell growth can trigger cell division by diluting the cell cycle inhibitor RB, which contributes to the maintenance of cell size homeostasis. The RB dilution mechanism relies on the cell cycle-dependent RB concentration dynamics, but the underlying mechanism is still unclear. On the other hand, cell cycle and cell size can feed back to regulate cell growth rate, of which the mechanisms are yet unknown. I found that the protein synthesis efficiency, a major determinant of cell growth efficiency, increases at the G1/S transition and decreases as cells grow larger within each cell cycle phase, suggesting that the global protein synthesis rate is actively regulated to facilitate cell cycle progression and cell size control. Here, in this proposal, I aim to address these gaps in our knowledge by determining the molecular mechanisms regulating RB concentration and global protein synthesis during cell cycle progression and cell growth. During the K99 phase, I’ve determined the molecular mechanisms underlying the RB concentration regulation during cell cycle progression (Aim1), which further revealed the molecular basis of how cell growth triggers cell division. During the R00 phase, I will continue to study how global protein synthesis is regulated during cell cycle progression (Aim2), which will help us understand how cell cycle regulates cell growth. These two aims link cell growth with cell division from the perspective of protein synthesis regulation. Then, the study on how protein synthesis is regulated during cell growth (Aim3), which will be pursued during R00 phase, explores the mechanism of how cell size feeds back to regulate growth rate. Thus, the three aims together set up a foundation towards a deeper understanding of the principles governing cell growth and proliferation. The completion of above aims will deepen our understanding of the fundamental molecular mechanisms regulating protein synthesis and cell growth rate, and therefore have broad impacts on cell and developmental biology. Moreover, this work will enhance our understanding of tissue regeneration deficiencies and tumorigenesis.