InterJournal Complex Systems, 1094
Status: Accepted
Manuscript Number: [1094]
Submission Date: 2004
Author(s): Maciej Swat ,Wojciech Swat ,Alexander Kel ,Hanspeter Herzel

Subject(s): CX.3



Mathematical models can contribute to an understanding of basic mechanisms determining the behavior of biological systems. This paper focuses on the role of small modules and feedbacks in two different cell biological systems. The first one is the gene-protein network governing the G1/S transition in the mammalian cell cycle. The second one is a postulated module responsible for actin remodeling in T-cells. Mutations in the first network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network. We identify various positive and negative feedback loops in the network controlling the G1/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator-inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G1/S phase transition point. We conclude that core modules can explain major features of the complex G1/S network and that they have robust decision taking function. The analysis of the second system is motivated by recent findings regarding actin remodeling. The binding of MHC (major histocompatibility complex) molecules to the TCR (T-cell receptor) complex is the primary signal for T-cell activation. Vav1 is an important signal transducer protein which is involved in the control of T-cell signaling and the organization of the actin cytoskeleton. We discuss the role of a truncated Vav1 protein in the formation of actin aggregates and caspase activation, both leading to apoptosis. As in the first model the bifurcation analysis reveals crucial modules of these processes. A threshold of caspase activation in terms of a transcritical bifurcation is discussed. Both models illustrate that complex regulatory networks can be understood by identifying elementary modules. References: Miletic AV, Swat M, Fujikawa K, Swat W. Cytoskeletal remodeling in lymphocyte activation. Curr Opin Immunol. 2003 Jun;15(3):261-8. Swat M, Kel A, Herzel H. Bifurcation Analysis of the Regulatory Modules of the Mammalian G1/S Transition. accepted for publication in Bioinformatics. Bluthgen N, Herzel H. How robust are switches in intracellular signaling cascades? J Theor Biol. 2003 Dec 7;225(3):293-300.

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