Regulation of cell cycle by Retinoblastoma protein: Systems Biology approach

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The purpose of the study is to identify the pathway regulating the activity of the tumor suppressor RB (retinoblastoma).

The retinoblastoma tumor suppressor gene

RB plays a major role in cell cycle entry: RB sequesters a family of transcription factors, E2Fs, responsible for the transcription of many genes involved in the cell cycle regulation, DNA replication and in the activation of the apoptotic pathway. RB functions as a brake in the cell cycle which is released when external signals (growth factors, …) inform the cell that it can proceed to S phase. The target of the external signals is the G1 cyclin/Cdk complex. Once active, the complex phosphorylates pRB which can then free E2F. E2F can then participate in the synthesis of many genes, among them, cyclin E, which immediately binds to the Cdc2 kinase Cdc2. The complex then fires DNA replication.

The understanding of the pathway regulating the tumor suppressor RB and the transcription factors E2F might give insight in the regulation of many cancers.

Constructing the pathway

Based on the literature, a quasi-exhaustive pathway has been built around RB to relate the regulation around the phosphorylation of the tumor suppressor protein. Once validated, the pathway can be exploited by computers to analyze deregulations observed in some cancers and used by biologists as a reference of the signalling pathways leading to RB phosphorylation.

The diagram allowed to integrate an important amount of information. However, the goal would also be to exploit these data in order to understand the pathway and anticipate the behaviour of any kind of mutations in the cell. For that purpose, different tools are available to manipulate this kind of diagrams (Cytoscape, BiNoM, ...).


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Modeling the pathway

The diagram was divided in different modules, each module representing a subpart of the diagram that describes the mechanism of modification (acetylation, phosphorylation) of a major protein in the cell cycle. The simplified diagram can be analyzed qualitatively (Boolean or discrete approaches) or quantitatively (ODEs) to provide a first understanding of the network.

What for?

The final purpose of the construction of this diagram is to provide a map of the RB pathway that can become a reference when studying different cancers and mutations.


This project was partly funded by the EC contract ESBIC-D (LSHG-CT-2005-518192), the PIC Retinoblastome from Institut Curie, the PIC Bioinformatique et Biostatistiques from Institut Curie and the Research Networks Program in Bioinformatics from the High Council for Scientific and Technological Cooperation between France and Israel (Ministere des Affaires Etrangeres, Ministere de l'Education Nationale, de l'Enseignement Superieur et de la Recherche).

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