SITCON Modeling signal transduction induced by a chimeric oncogene (nov.2006-nov.2009)


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Summary

Cellular models provide possibility to get insights into the complex picture of deregulations happening in cancer cells. The Ewing inducible cellular model is a cell line characterized by a malignant genomic translocation and appearance of a chimeric gene EWS/FLI-1 whose activity leads to the uncontrolled cell growth. A system was designed in which this chimeric gene can be effectively silenced and switched on back, resulting in arresting and launching cell proliferation. Thus the expression of the only gene changes cell phenotype from tumorigenic to the normal one in fully reversible and controlled manner. However, the biological mechanisms by which the expression of this oncogene regulates cell proliferation remain unclear. To study them, a comprehensive corpus of data including results of genomic, transcriptome (time-series and steady state measurements), ChIP-chip and microRNA arrays is already collected for this system and the new data will be available in the following year.

The principal goals of the project are:

  1. Using the data collected in high-throughput experiments and genetic network inference methods, reconstruct the interaction network through which the chimeric protein EWS/FLI-1 affects cell cycle and apoptosis;
  2. Determine the signal transduction pathways involved in passing the signal from EWS/FLI-1 to the cell cycle and apoptotic genes;
  3. Create a detailed model of the functioning of the identified pathways in the context of the Ewing system and understand the details of the difference in their behavior in comparison with the normal context;
  4. Use modeling to propose new experiments in order to validate and improve the constructed models and perform these experiments.