Abstract
Undifferentiated embryonic stem cells proliferate under a unique cell cycle program characterized by truncated G1 phase. Molecular basis for this unique cell cycle regulation and how it is related to their pluripotency are still elusive. In mouse embryonic stem cells, Cdc6, ASK(activation subunit for Cdc7), CyclinA1 and CyclinB2 proteins are highly overexpressed, and their protein levels decrease upon induction of differentiation. This is mainly caused by highly abundant Emi1 protein which inhibits ubiquitin ligase APC, since downregulation of Emi1 reduces the levels of ASK, CyclinA and CyclinB in ES cells. Emi1 expression is regulated by E2F, which is constitutively active in ES cells. We propose that a positive feedback loop involving active E2F and Emi1-mediated activation of Cdk activities may be a part of the system which permits unique ES cell cycle. Indeed, Emi1 depletion causes increased levels of CycinD2 and unphosphorylated forms of Rb, the hallmarks of G1 phase, Experiments with the Fucci (fluorescent cell cycle indicator) ES cells also indicate that depletion of Emi1 leads to appearance of cells with G1 features. Currently, effects of manipulation of the Emi1 protein level on the pluripoitency or differentiation processes are being examined. A possibility to manipulate pluripotency and differentiation potential by regulating cell cycle will be discussed.
