Project 4: Putting pieces together

Project 1: MAP kinase pathway

Project 2: entry in S phase

Project 3: apoptosis

1. You will have one more week to interact with the other groups and get the information necessary to complete your project. The purpose of this project is to build a full model of the different modules developed by the other groups (projects 1, 2 and 3).

2. You will need to find the common proteins among the different modules and change them into variables in the appropriate cases. List the molecules that interact in other modules and describe how you made the links.

3. Show the diagram of protein intercations using Graphviz (see Biocham documentation for help).

4. Plot the simulation. You don't have to show all the molecules. The most important are : K~{p1,p2}, CycE, CycD, E2F, Rb, p53, p21, p27, p16, and Myc.

5. Once the modules are assembled into a consensus model, you will test the full model by simulating some mutations. For example, show what happens when:
- the growth factors (Signal) are deprived.
- Rb is deleted (don't forget to set initial value to 0).
- the growth factors are deprived and Rb are deleted. Considering that CycD is a sensor of growth factors and the starter for the G1 to S transition, and CycE starts the synthesis of DNA, what can you deduce in this mutant?
- MYC is overexpressed slightly (10-fold) or a lot (100-fold). Delete the effect of E2F, and increase only the unregulated synthesis of Myc (ksp).

6. In the p53 module, for simplicity, we consider that when p53 is activated, apoptosis is induced. We know that this fact is wrong. There is a mechanism that attempts to lower p53 in response to DNA repair for example. If p53 activity cannot be lowered after a certain amount of time, apoptosis occurs.
What effect on the cell cycle does p53 have? What would happen in the cell cycle when DNA is repaired? A lot of cancers are related to p53 and to Rb. Using the results of the mutations you observed in (5), explain what effect mutations on Rb will have? What about p53?

For a reference you can read :
Model from Aguda and Tang (2003) A structural analysis of the qualitative networks regulating the cell cycle and apoptosis. Cell Cycle, 2: 6, 538-544. [Abstract] [PDF]