G1 cyclins protect pluripotency

Abstract

G1 cyclins are considered essential for DNA replication and cell division. A recent report now shows that some cells can cycle in the absence of G1 cyclins. In embryonic stem cells and cancer cells, G1 cyclins are required to activate cyclin-dependent kinases to phosphorylate core pluripotency factors and maintain pluripotency.

Figure 1

G1 cyclins and cyclin-dependent kinases in cell cycle progression and maintenance of pluripotency in mESCs. (a) In the canonical model cyclin D activates CDK4/6 and phosphorylates RB in early/mid-Gl and cyclin E hyperphosphorylates RB in late Gl. This leads to the release of E2F transcription factors, the expression of cell cycle genes, and progression through S phase, (b) The proportional length of cell cycle phases and expression levels of cyclins in wild-type (WT) and Gl cyclin Q-KO MEFs and mESCs. MEFs are characterized by a cell-cycle-specific expression profile of cyclins and a long G1 phase, whereas mESCs have a short G1 phase and express cyclins in a cell-cycle-independent fashion, except for cyclin B. The Q-KO of G1 cyclins stalls the cell cycle in MEFs, while it prolongs G1 phase without having a significant impact on cell proliferation in mESCs. (c) Cyclin E-CDK2 protects core pluripotency factors from degradation in mESCs. Cyclin E activates CDK2 and leads to phosphorylation of RB and the pluripotency factors Oct4, Sox2 and Nanog. Phosphorylated pluripotency factors are bound by Pin1, which protects them from ubiquitination (Ub) and proteasomal degradation. Degradation of pluripotency factors in G1 cyclin Q-KO mESCs leads to upregulation of the trophectoderm marker Cdx2, which is usually repressed by Oct4. WT mESCs normally contribute to the embryo proper in chimaera assays, but G1 cyclin Q-KO mESCs contribute primarily to the placenta and neural lineages. RB proteins exist almost exclusively in the hyperphosphorylated state in mESCs due to high CDK2 activity.