Regulation of G1 Cell Cycle Progression: Distinguishing the Restriction Point from a Nutrient-Sensing Cell Growth Checkpoint(s)

Most genetic changes that promote tumorigenesis involve dysregulation of G1 cell cycle progression. A key regulatory site in G1 is a growth factor-dependent restriction point (R) where cells commit to mitosis. In addition to the growth factor-dependent "R," which maps to a site about 3.5 hours after mitosis, there is another checkpoint later in G1 that is dependent on nutritional sufficiency that has also been referred to as R. However, this second site in late G1 can be distinguished both temporally and genetically from R. We are proposing that the late G1 regulatory site be more appropriately referred to as a "cell growth" checkpoint to distinguish it from R. This checkpoint, which likely has an evolutionary relationship to the yeast cell cycle checkpoint START, is regulated by signals governed by mTOR, the mammalian target of rapamycin. This review summarizes evidence that distinguishes R from the proposed cell growth checkpoint. Since both checkpoints are dysregulated in most, if not all, human cancers, distinguishing between these 2 distinct G1 regulatory checkpoints has significance for rational therapeutic strategies targeting oncogenic signals.