A study of cell growth, division and programmed differentiation by simulation and experiments

Deregulation of cellular mechanisms responsible for cell growth, reproduction and differentiation is one of the hallmarks of all cancers. This study aims to elucidate the mechanisms underlying cell growth and differentiation using innovative computational and experimental tools. In the current study, we first review the basic cell cycle mechanisms in a typical eukaryotic cell (Chapter 1). In chapter 2, we analyze three published cell-cycle models and test our hypothesis that cell-cycle control architecture follow the "robust yet fragile" or the Highly Optimized Tolerance (HOT) paradigm. A very important fragile sub-system in the cell-cycle, revealed in our analysis of the cell-cycle models is protein translation. In chapter 3, we study the process of protein translation in detail, especially protein translation initiation. We formulate a detailed, mechanistic model of translation initiation from interactions validated in the literature. Novel systems-biology tools such as coupling analysis are developed and employed to gain insight into critical components of translation initiation. This study reveals the importance of the Akt and mTOR proteins in the presence of growth factors and that of negative regulators such as PTEN and 4E-BP1 in their absence. Differentiation is the process by which a less specialized cell becomes more committed in its lineage, in response to the external environment. Chapter 4 presents an experimental study of Arsenic Trioxide on Human Leukemia (HL-60) myeloblastic cells. Our results show that Arsenic Trioxide enhances All Trans Retinoic Acid (ATRA) induced differentiation of HL-60 cells. This increase in differentiation is associated with an increase in the sustained Mitogen Activate Protein Kinase (MAPK) response. Chapter 5 presents an ensemble approach to model the response of HL-60 cells to ATRA and the role of sustained MAPK in differentiation. The model and its analysis present a systematic method to understand mechanisms involved in programmed cell differentiation in adult stem cells. In Chapter 6, we present a model combining hormone growth factor receptor signaling and prostate specific antigen (PSA) in LNCaP prostate adenocarcinoma cells. Finally, the concluding chapter discusses future directions of the current study.