Controlling Depth of Cellular Quiescence by an Rb-E2F Network Switch
Development, tissue renewal and longevity of multi-cellular organisms require the ability to switch between a proliferative state and quiescence, a reversible arrest from the cell cycle. Stem cells are quiescent but retain the ability to re-enter the cell cycle to self-renew or to differentiate and re-populate the tissue. Abnormal quiescence depth is common in human disease and maintaining the correct depth is critical to the normal functions of various cell types and tissue homeostasis. In the first study we investigate the cellular properties associated with deep and shallow quiescence and the Rb-E2F activation threshold in the cell as a determinant of quiescence depth. Through model simulations and experimental measurements, we demonstrate that the cellular modifiers in the Rb-E2F pathway control quiescence depth with varying efficacy. Together, the data show that the parameters in the Rb-E2F pathway modulate both deep and shallow quiescence and represent an important control mechanism of cellular quiescence.
The Rb-E2F pathway interacts with diverse cellular pathways that respond to environmental signals to together modulate quiescence depth. Given that some circadian clock genes (e.g., Cry) affect key components in the Rb-E2F pathway, we tested the effect of upregulated Cry activity on quiescence depth regulated by the Rb-E2F bistable switch. Next, we constructed a mathematical model that represents a large array of potential interactions between circadian regulators and the Rb-E2F bistable switch, and computationally searched for links that explain the experimental observations. Our modeling results show that Cry activation leads to increased cyclin dependent kinase inhibitor (e.g., p21) activity, which in turn drives cells into deeper quiescence. Collectively, the data shows that the model prediction and my experimental results support this interaction and allows us to further understand the diverse cellular interactions that jointly control quiescence depth.
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