MAPK cell-cycle regulation in Saccharomyces cerevisiae and Candida albicans.

The cell cycle is the sequential set of events that living cells undergo in order to duplicate. This process must be tightly regulated as alterations may lead to diseases such as cancer. The molecular events that control the cell cycle are directional and involve regulatory molecules such as cyclins and cyclin-dependent kinases (CDKs). The budding yeast Saccharomyces cerevisiae has become a model to study this complex system since it shares several mechanisms with higher eukaryotes. Signal transduction pathways are biochemical mechanisms that sense environmental changes and there is recent evidence that they control the progression through the cell cycle in response to several stimuli. In response to pheromone, the budding yeast arrests the cell cycle in the G1 phase at the START stage. Activation of the pheromone response pathway leads to the phosphorylation of Far1, which inhibits the function of complexes formed by G1 cyclins (Cln1 and Cln2) and the CDK (Cdc28), blocking the transition to the S phase. This response prepares the cells to fuse cytoplasms and nuclei to generate a diploid cell. Activation of the Hog1 MAP kinase in response to osmotic stress or arsenite leads to the transient arrest of the cell cycle in G1 phase, which is mediated by direct phosphorylation of the CDK inhibitor, Sic1, and by downregulation of cyclin expression. Osmotic stress also induces a delay in G2 phase by direct phosphorylation of Hsl7 via Hog1, which results in the accumulation of Swe1. As a consequence, cell cycle arrest allows cells to survive upon stress. Finally, cell wall damage can induce cell cycle arrest at G2 via the cell integrity MAPK Slt2. By linking MAPK signal transduction pathways to the cell cycle machinery, a tight and precise control of the cell division takes place in response to environmental changes. Research into similar MAPK-mediated cell cycle regulation in the opportunistic pathogen Candida albicans may result in the development of new antifungal therapies.