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 (ras2G19V) 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 whichras2G19Vinfluences cell size are unknown. Here, we found thatras2G19Vinhibits a critical step in cell cycle entry, in which an early G1 phase cyclin induces transcription of late G1 phase cyclins. Thus,ras2G19Vdrives 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.ras2G19Vinfluences 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,ras2G19Vappears 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.

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 (ras2G19V) 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 ras2G19V influences cell size are unknown. Here, we found that ras2G19V inhibits a critical step in cell cycle entry, in which an early G1 phase cyclin induces transcription of late G1 phase cyclins. Thus, ras2G19V 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. ras2G19V influences transcription of late G1 phase cyclins via a poorly understood step in which Cln3 inactivates the Whi5 transcriptional repressor. Previous studies found that yeast Ras relays signals via protein kinase A (PKA); however, ras2G19V appears to influence late 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. Hyperactive Ras also influences expression of G1 phase cyclins in mammalian cells, but the mechanisms remain unclear. Further analysis of Ras signaling in yeast could lead to discovery of new mechanisms by which Ras family members control expression of G1 phase cyclins.