Project Summary/Abstract 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 synthesis of RB protein, but the mechanism regulating RB synthesis 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 . Crucially, both RB1 mRNA and total mRNA concentrations are not cell cycle-dependent, implying previously unknown translational mechanisms. Here, in this proposal, I aim to address these gaps in our knowledge by determining the molecular mechanisms regulating RB synthesis and global protein synthesis during cell cycle progression and cell growth. The investigation of RB protein synthesis during cell cycle progression (Aim1) will further reveal the molecular basis of how cell growth triggers cell division, and the study on global protein synthesis during cell cycle progression (Aim2) 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) 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. With the help of an outstanding team of mentors, collaborators, and consultants, I will train in the cutting-edge technologies in quantitative biology and molecular biology, and acquire skills for my career development. Together, the proposed scientific and training program form a strong foundation for an independent research career in understanding the principles of cell growth under physiological and pathological conditions.

Project Narrative The protein synthesis rate changes with cell size and cell cycle stage, but the underlying mechanisms are poorly understood. This project will identify the molecular mechanisms controlling RB protein synthesis and global protein synthesis during cell cycle progression and cell growth in mammalian cells. This will deepen our understanding of cell growth principles, and yield insight into disease states arising from abnormal cell growth such as tissue regeneration deficiencies and cancer development.