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

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 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, ras2(G19V) 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.