Mathematical modeling of pathways involved in cell cycle regulation and differentiation

Abstract

Cellular processes critical to sustaining physiology, including growth, division and differentiation, are carefully governed by intricate control systems. Deregulations in these systems often result in complex diseases such as cancer. Hence, it is crucial to understand the interactions between molecular players of these control systems, their emergent network dynamics, and, ultimately, the overall contribution to cellular physiology. In this dissertation, we have developed a mathematical framework to understand two such cellular systems: an early checkpoint (START) in the budding yeast cell cycle (Chapter 1), and the canonical Wnt signaling pathway involved in cell proliferation and differentiation (Chapter 2). START transition is an important decision point where the cell commits to one round DNA replication followed by cell division. Several years of experimental research have gone into uncovering molecular details of this process, but a unified understanding is yet to emerge. In chapter one, we have developed a comprehensive mathematical model of START transition that incorporates several findings including information about the phosphorylation state of key START proteins and their subcellular localization. In the second chapter, we focus on modeling the canonical Wnt signaling pathway, a cellular circuit that plays a key role in cell proliferation and differentiation. The Wnt pathway is often deregulated in colon cancers. Based on some evidence of bistability in the Wnt signaling pathway, we proposed the existence of a positive feedback loop underlying the activation and inactivation of the core protein complex of the pathway. Bistability is a common feature of biological systems that toggle between ON and OFF states because it ensures robust switching back and forth between the two states. To study and explain the behavior of this dynamical system, we developed a mathematical model. Based on experimentally determined interactions, our simple model recapitulates the observed phenomena of bimodality (bistability) and hysteresis under the effects of the physiological signal (Wnt), a Wnt-mimic (LiCl), and a stabilizer of one of the key members of core complex (IWR-1). Overall, we believe that cell biologists and molecular geneticists can benefit from our work by using our model to make novel quantitative predictions for experimental verification.