Protein geranylgeranylation, not farnesylation, is required for the G₁ to S phase transition in mouse fibroblasts

In order to assess the relative contributions of farnesylated and/or geranylgeranylated proteins on cell cycle progression from G₁ to S phase we designed potent and selective farnesyltransferase (FTI-277) and geranylgeranyltransferase-I (GGTI-298) inhibitors. Flow cytometry studies showed that treatment of NIH3T3 cells with GGTI-298 or lovastatin, which inhibits both protein farnesylation and geranylgeranylation, arrested cells in G₀/G₁ whereas cells treated with FTI-277 progressed normally through the cell cycle. [³H]thymidine incorporation studies showed that mevalonate and geranylgeraniol, but not farnesol, released the lovastatin G₁ block. Furthermore, mevalonate release of the lovastatin G₁ block was inhibited by GGTI-298 but not by FTI-277. These results demonstrate that geranylgeranylated proteins are required for cells to proceed from G₁ to S phase, and that farnesylated proteins do not play an essential role in the G₁ to S phase transition.