Hyperactive Ras disrupts cell size control and a key step in cell cycle entry in budding yeast

Abstract Severe defects in cell size are a nearly universal feature of cancer cells. However, the underlying causes are unknown. A previous study suggested that a hyperactive mutant of yeast Ras ( ras2 G19V ) that is analogous to the human Ras oncogene causes cell size defects, which could provide clues to how oncogenes influence cell size. However, the mechanisms by which ras2 G19V influences cell size are unknown. Here, we found that ras2 G19V inhibits a critical step in cell cycle entry, in which an early G1 phase cyclin induces transcription of late G1 phase cyclins. Thus, ras2 G19V drives overexpression of the early G1 phase cyclin Cln3, yet Cln3 fails to induce normal transcription of late G1 phase cyclins, leading to delayed cell cycle entry and increased cell size. ras2 G19V influences transcription of late G1 cyclins via a poorly understood step in which Cln3 inactivates the Whi5 transcriptional repressor. Previous studies found that Ras relays signals via protein kinase A (PKA) in yeast; however, ras2 G19V appears to influence G1 phase cyclin expression via novel PKA-independent signaling mechanisms. Together, the data define new mechanisms by which hyperactive Ras influences cell cycle entry and cell size in yeast. Expression of G1 phase cyclins is also strongly influenced by mammalian Ras via mechanisms that remain unclear. Therefore, further analysis of PKA-independent Ras signaling in yeast could lead to discovery of conserved mechanisms by which Ras family members control expression of G1 phase cyclins.