Morphogenetic checkpoint of the budding yeast cell cycle

In budding yeast, the morphogenetic checkpoint (MCP) relies upon inhibitory phosphorylation of Cdc2/Cyclin B by Swe1 to condition entry into mitosis to the formation of a bud. Taking inspiration in the ODE model published by Ciliberto et al. (2003) [1], we have developed a logical model of the MCP, with the aim to plug it to our core engine of the budding yeast cell cycle (cf. [2]).

The activity of Cdc28/Clb2 is controlled by the balance between Swe1 and Mih1. Swe1, the budding yeast homologue of the tyrosine kinase wee1, inhibits Cdc28 by phosphorylation, whereas the phosphatase Mih1 (homologue of Cdc25) removes the inhibitory phosphate. Swe1 itself is inhibited by phosphorylation by Cdc28/Clb2, in a positive feed-back loop. Based on Ciliberto's model, we assume that Swe1 is also somehow modified by Hsl1, a protein kinase activated by bud formation, and that this modification of unknown nature - as Swe1 does not appear to be a substrate of Hsl1- has an inhibitory effect on Swe1. The checkpoint is reinforced by a MAPK pathway that inhibits Mih1 through Mpk1 activity in absence of a bud. An important point of the MCP is the possibility for the cell to undergo adaptation, that is to evade the checkpoint and enter mitosis in absence of a bud after some time. Ciliberto's model supports the hypothesis that failure to make a bud creates a second threshold for mass for the G2-M transition (the first threshold being at Start). Mass impacts cell progression by increasing the synthesis of the cyclins, and in particular CycB that is required for entry into mitosis (see the core model -LINK- for details). Here, we have introduced a second threshold for the MASS variable, to represent the idea that increased CycB synthesis can yield enough CycB activity to overcome inhibition by Swe1. Our model accounts for the wild-type as well as 14 mutants phenotypes described by Ciliberto et al. and in Harrison et al (2001) [3] in terms of entry into mitosis – monitored by Clb2 activation. This model has then been to our model of the core cell cycle engine of the budding yeast (see coupled model).

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