Molecular Mechanisms of Cell Cycle Control

Univ Of Massachusetts Med Sch Worcester, Worcester MA

Investigators

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Abstract

ABSTRACT Regulated progression through the cell cycle is essential for normal development and to prevent uncontrolled proliferation that can lead to cancer. The focus of my laboratory is to understand the molecular mechanisms that control cell growth and division, with the goal of understanding how mutations in the cell cycle-regulatory network contribute to disease. To accomplish this, we take molecular and systems level approaches in budding yeast to gain mechanistic insights into cell cycle regulation, and later to probe the conservation of these mechanisms in human cells. The current proposal focuses on two key unanswered questions. First, how does multisite phosphorylation regulate protein function to drive cell cycle progression? Cyclin dependent kinases (CDKs) phosphorylate hundreds of proteins to orchestrate the cell cycle, but how they regulate most substrates is not known. We recently developed a high-throughput approach that can dissect multisite phosphorylated domains to discern the contributions of each individual site to the regulation of protein function. We will use this approach to investigate how CDK regulates its protein substrates and to determine how multisite phosphorylation impacts the activities of human transcription factors to drive proliferation. Second, is cell cycle regulation important for cells to adapt and survive in stressful environments? Cells transiently arrest the cell cycle when they are exposed to environmental stress, and after they adapt to the stressor the cell cycle resumes at a slower rate. We will elucidate the mechanisms that control adaptation to chronic stress and investigate the importance of cell cycle regulation for adaptation and survival. Stress responses not only ensure that healthy cells can survive in challenging environments, but they also contribute to disease by enabling cells to survive where they shouldn't and providing resistance to therapies. Our findings may suggest strategies to disrupt adaptation in disease contexts. In addition, this project will uncover conserved mechanisms that control proliferation, potentially offering targets for intervention in cancer cells.