UC Santa Cruz

Severe defects in cell size are a nearly universal feature of cancer cells. Yet, the mechanisms that drive size defects in cancer cells remain unknown, and it is unclear whether they are a direct consequence of primary oncogenic drivers or a secondary consequence of mutations that accumulate during evolution of cancer cells. Hyperactive mutants of Ras are amongst the most prevalent oncogenic drivers. In budding yeast, previous studies have suggested that hyperactive versions of the Ras homolog (ras2G19V) cause defects in cell size. However, the mechanisms by which ras2G19V drives cell size defects are unknown, and it is unclear whether the size defects are due to accumulation of suppressor mutations. Here, I developed a system for inducible expression of ras2G19V that allows for investigation into the immediate consequences of ras2G19V expression. I found that ras2G19V causes a delay in G1 phase, increased cell size, and aberrant expression of G1 cyclin proteins. Furthermore, ras2G19V appears to inhibit a key step in cell cycle entry, in which an early G1 cyclin induces transcription of late G1 cyclins. The data further suggest that Ras does not influence cell size solely via effects in G1 phase. Finally, we found that expression of oncogenic Ras alone is sufficient to cause cell size defects in NIH 3T3 cells, which suggests that defects in cell size in cancer cells could be a direct consequence of primary oncogenic signals. Together, the data suggest that hyperactive forms of Ras influence cell size in both yeast and mammals. Further analysis will determine whether Ras influences cell size via conserved mechanisms.