Entry into the cell cycle is deregulated in nearly all types of cancer, demonstrating the importance of the cellular decision to proliferate or remain quiescent. Despite this, the molecular events involved in a cell's committing to another round of cell division are not well defined. The overall goal of this proposal is to build a quantitative, dynamic, and mechanistic understanding of the proliferation-quiescence decision in normal, somatic cells. Specifically, I am interested in how cells integrate stress and growth factor signaling inputs at the end of the previous cell cycle to control the proliferative or quiescent fae after mitosis. Key to achieving this goal is my ability to monitor cell cycle events at the moleculr level in single, asynchronously cycling cells. I will make use of a new live-cell sensor that I developed that monitors Cyclin-dependent kinase 2 (CDK2) activity, a key driver of cell cycle progression. Cell cycle commitment is marked by a buildup of CDK2 activity, whereas quiescent cells lack CDK2 activity.
My first aim will be to determine how the CDK inhibitor, p21, controls whether, after mitosis, cells immediately build up CDK2 activity and choose a proliferative fate or turn CDK2 activity off and choose a quiescent fate.
My second aim will explore the dynamics with which DNA damage causes cell cycle arrest, how cells recover from this damage and resume cycling, and how DNA damage in one cell cycle affects the proliferation-quiescence decision in the next cycle. In my third aim, I seek to understand how growth factor signaling regulates the cell cycle machinery to drive proliferation and how mitogenic signals are integrated in G2/M of the previous cell cycle to influence the proliferative or quiescent fate of a cell. My ability to link upstream signal transduction events to the proliferation-quiescence outcome in single cells will provide valuable insight into this critical control point and may identify new targets that be exploited therapeutically for treating cancer.

Public Health Relevance

The work outlined in this proposal will provide new insights into the regulation of proliferation pathways and how these pathways are corrupted in cancer. A better understanding of how normal cells switch between proliferation and quiescence will shed light on cells become tumorigenic and reveal new possibilities for therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K22)
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Jakowlew, Sonia B
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Moser, Justin; Miller, Iain; Carter, Dylan et al. (2018) Control of the Restriction Point by Rb and p21. Proc Natl Acad Sci U S A 115:E8219-E8227
Miller, Iain; Min, Mingwei; Yang, Chen et al. (2018) Ki67 is a Graded Rather than a Binary Marker of Proliferation versus Quiescence. Cell Rep 24:1105-1112.e5
Gookin, Sara; Min, Mingwei; Phadke, Harsha et al. (2017) A map of protein dynamics during cell-cycle progression and cell-cycle exit. PLoS Biol 15:e2003268
Arora, Mansi; Moser, Justin; Phadke, Harsha et al. (2017) Endogenous Replication Stress in Mother Cells Leads to Quiescence of Daughter Cells. Cell Rep 19:1351-1364