A data integration approach for cell cycle analysis oriented to model simulation in systems biology

Abstract

Background: The cell cycle is one of the biological processes most frequently investigated in systems biology studies and it involves the knowledge of a large number of genes and networks of protein interactions. A deep knowledge of the molecular aspect of this biological process can contribute to making cancer research more accurate and innovative. In this context the mathematical modelling of the cell cycle has a relevant role to quantify the behaviour of each component of the systems. The mathematical modelling of a biological process such as the cell cycle allows a systemic description that helps to highlight some features such as emergent properties which could be hidden when the analysis is performed only from a reductionism point of view. Moreover, in modelling complex systems, a complete annotation of all the components is equally important to understand the interaction mechanism inside the network: for this reason data integration of the model components has high relevance in systems biology studies.

Description: In this work, we present a resource, the Cell Cycle Database, intended to support systems biology analysis on the Cell Cycle process, based on two organisms, yeast and mammalian. The database integrates information about genes and proteins involved in the cell cycle process, stores complete models of the interaction networks and allows the mathematical simulation over time of the quantitative behaviour of each component. To accomplish this task, we developed, a web interface for browsing information related to cell cycle genes, proteins and mathematical models. In this framework, we have implemented a pipeline which allows users to deal with the mathematical part of the models, in order to solve, using different variables, the ordinary differential equation systems that describe the biological process.

Conclusion: This integrated system is freely available in order to support systems biology research on the cell cycle and it aims to become a useful resource for collecting all the information related to actual and future models of this network. The flexibility of the database allows the addition of mathematical data which are used for simulating the behavior of the cell cycle components in the different models. The resource deals with two relevant problems in systems biology: data integration and mathematical simulation of a crucial biological process related to cancer, such as the cell cycle. In this way the resource is useful both to retrieve information about cell cycle model components and to analyze their dynamical properties. The Cell Cycle Database can be used to find system-level properties, such as stable steady states and oscillations, by coupling structure and dynamical information about models.

Figure 1

The database integration system. In this figure the resources which have been chosen for the development of the Cell Cycle Database are shown. The resources from which data are taken are shown in the green box, while the resources which are provided only as external links are presented in the blue box.

Figure 2

The protein report for Cell division protein kinase 2 (Cdk2). The protein report for the Cyclin-dependent Kinase 2 (CDK2) shows the main information users can retrieve related to this protein and external links to other different resources. In the protein report users can find many interesting information about CDK2, such as the graphical visualization of the protein domains. A list of the models in which CDK2 is involved is also shown on the protein report.

Figure 3

The mathematical model section. The SBML model section in which the Differential Equation system is shown from the model of Swat et al 2004 (usually it appears in a pop-up window when the user chooses to visualize the DE system from the web interface). The web interface allows the user to decide which SBML components to show through an HTML form based on check-buttons.

Figure 4

The model simulation section. The simulation section with a representation of a time course graph of some components of the cell cycle model from Swat et al 2004. Using the web interface it is possible to select which model component will be shown: in this case the graph plots the time course for the CyclinE-Cdk2 complex concentration in the inactive state (CycEi), the CyclinE-Cdk2 complex concentration in the active state (CycEa) versus the time course for pRB and E2F1 concentrations.