Final Project – Alicia Grande – Using the incoherente feedforward loop idea for explain cell cycle reentry during pheromone response

In haploid yeast, mating pheromone triggers a fate decision: arrest of the cell cycle in G1 and initiation of mating events. To do that, the MAP kinase of the pheromone response pathway (PRP) Fus3 activates the cyclin dependent kinase inhibitor Far1, which binds to and inhibits all three G1 cyclins complexes, Cdc28/Clns. Cdc28/Cln2 activity is essential to pass the START G1 checkpoint, while Cdc28/Cln3 is required earlier in G1 to drive the expression of Cln2. This has two important consequences: a) inhibition of Cdc28/Clns causes cells to arrest in G1, and b) since Cdc28/Cln2 can block pheromone response, its inhibition by Far1 acts as a positive feedback loop.

However, when cells are exposed to low doses of pheromone a new phenotype appears: some cells start responding to pheromone but after some time, stop the response and divide. We named this behavior “switching cells”

We know this switching behavior is present in cln1cln2 strain but absent in Kar4 strain. Kar4 is a transcription factor induced by pheromone and involved in karyogamy. Kar4 induces, with a time delay, the transcription of Cln3 (cyclin of G1). Therefore, my hypothesis is that the pheromone triggers not only the activation of the pheromone pathway but also, with a delay, the increase of Cln3 (cyclin of G1).

Using Copasi and the idea of a incoherent feedforward loop I built a toy model in order to understand how this two opposite branches can explain dynamically the switching behavior.

The goal is to use the insight that I won with the toy model to build a more realistic model for the pheromone pathway and the activation of Cln3 by pheromone.

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