The ability to switch between proliferation in a yeast form and development into a hyphal (mold) form is a hallmark of C. albicans. The switch to hyphal growth depends on external inducing conditions, but its efficiency is affected by the internal physiological state of the cell: for example, quiescent, stationary phase cells are induced to form hyphae more readily than proliferating cells. Ume6, a transcription factor that is transcriptionally induced under hyphal-promoting conditions, is both necessary and sufficient for hyphal morphogenesis. We find that Ume6 is post-transcriptionally regulated by the cell cycle kinase Cdc28/Cdk1. Our data suggest that different Cdc28 cyclins reduce Ume6 activity via different mechanisms. One mechanism involves degradation of Ume6 via the activity of the SCFCDC4 ubiquitin ligase, a complex that typically requires phosphorylation of the substrate. HGC1, the Cdc28 cyclin gene involved in hyphal morphogenesis, is a key transcriptional target of Ume6. We find that Hgc1/Cdk1 is the kinase required for Ume6 degradation in C. albicans, resulting in a negative feedback loop between Hgc1 and Ume6. A second mechanism involves Cln3, a G1 cyclin that is essential for cell cycle progression and yeast proliferation. Our data indicate that Cln3 activity is able to antagonize the activity of Ume6 in the heterologous S. cerevisiae system, and that Cln3 suppresses the induction of hyphal morphogenesis by Ume6 in C. albicans. This observation suggests that Cln3 activity may explain the antagonistic relationship between yeast proliferation and hyphal development in C. albicans.
