p27 Kip1 is a critical regulator of the eukaryotic cell cycle. It acts as a checkpoint protein and regulates cell cycle progression at the G1 and G1/S phase as well as predominantly blocks cell cycle progression in the absence of growth factors. Intracellular turnover of p27 is tightly regulated at the level of translation as well as by posttranslational modification. The mechanism by which p27 protein is rapidly degraded during the G1 and G1/S phase transition is well characterized. However, the process by which p27 remains extremely stable in the absence of growth factors remains unknown. Here, we report that GSK-3 dependent phosphorylation of p27 protein is essential for its enhanced stability. p27 protein harbors two functional GSK-3 phosphorylation sites at the C- terminus, which was found to be effectively phosphorylated by the cognate enzyme both in vitro and in vivo. Combined with earlier observation which shows that it phosphorylates and triggers cyclin D degradation; GSK-3 now appears to be a central mediator of the cell-cycle regulatory network, where it acts as a two-way switch, phosphorylating and targeting pro-proliferative factors for degradation on one hand and simultaneously phosphorylating and stabilizing an anti-proliferative factor on the other hand. This dual mode of activity may doubly ensure that cell cycle progression is aptly prohibited under conditions of limited growth factor availability.
- Lithium chloride
- p27 phosphorylation
- p27 stability
- Post-translational modification
- Protein kinase B