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Jeudi 26 janvier 2012 - Laurence Calzone (Institut Curie, Paris) Print
Written by Pierre PETERLONGO   

Logical modelling of bladder tumorigenesis

10h30 Salle Aurigny

The E2F transcription factors are key regulators of the cell cycle. The E2F family members are categorized in two sections, the activators (E2F1, E2F2, E2F3a) and the inhibitors (E2F3b, E2F4, E2F5, E2F6, E2F7, E2F8) of proliferation. Most of these transcription factors are inhibited by the pocket proteins, RB and p107, during G0 and G1 phases and are released at the G1/S transition by phosphorylation and inactivation of the RB-like proteins. We concentrate on E2F1, which is involved in both proliferation and apoptosis. 

We built two networks, the first one is a descriptive reaction network showing the molecular links between RB and p53 pathways and the involvement of the E2F1 and E2F3 transcription factors and the second one is an influence network derived from the first reaction map. The reaction network includes 56 species (14 proteins, 14 mRNA, 13 genes), 4 inputs (DNA damage, EGFR, FGFR3, and TGFb) and 64 reactions. The corresponding influence network was reduced to 14 species, 4 inputs and 3 outputs (apoptosis, proliferation and growth arrest). 

A mathematical model based on logical formalism was translated from the influence network. The dynamical model accounts for diverse phenotypes of both normal and mutant cells found in the literature in response to growth and DNA damage signals.  Moreover, the model verifies the hypotheses on how a cell becomes invasive in bladder tumours, through which signalling pathways and with which type of alterations or mutations invasiveness is associated in two different contexts, the FGFR3 mutated cells and the FGFR3 not mutated cells. We also perform explorative studies on expression data for the genes of the network. This work is in progress and the analysis is still exploratory.

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