105ES cells are characterised by high Cdk2 activity and elevated levels of both cyclins A
and E throughout the cell cycle (Fujii-Yamamoto et al. 2005 ). Increased levels of cyclins
in interphase might account for the shortened G1 phase in ES cells and their accelerated
cell cycle progression (Fujii-Yamamoto et al. 2005 ; Nichols et al. 1998 ; Yang et al.
2011 ). In pluripotent ES cells of the ICM, Cdk1/cyclin-B seems to be the only Cdk
activity that is regulated in a cell cycle-dependent manner (Stead et al. 2002 ). Interestingly,
the levels of the APC/C inhibitor Emi1 (highly homologous to XErp1) are increased in
mouse ES cells compared to somatic cells (Ballabeni et al. 2011 ), and its ability to
inhibit the APC/CCdh1 during interphase seems to be important for the shortened G1
phase in ES cells and their pluripotent characteristic. It has been suggested that in addi-
tion to muted APC/C activity, high E2F-dependent transcriptional activities in ES cells
result in hyperaccumulation of DNA replication-licensing factors such as Cdt1, which
promotes rapid entry into S-phase after M-phase exit (Ballabeni et al. 2011 ). Increased
levels of Emi1 in ES cells cause the accumulation of an APC/CCdh1 substrate: geminin.
Geminin is well known for its function in limiting DNA replication to once per cell cycle
by binding to and inhibiting Cdt1 (Wohlschlegel et al. 2000 ; Nishitani and Lygerou
2002 ). Recent studies revealed that geminin not only prevents the reinitiation of DNA
replication but also functions as a transcriptional regulator (Del Bene et al. 2004 ; Luo
et al. 2004 ), and this function seems to be important to maintain the pluripotent state of
ES cells (Yang et al. 2011 , 2012 ). Geminin levels in trophoblast cells are significantly
lower than in pluripotent ES cells (Gonzalez et al. 2006 ), and the depletion of Emi1 or
geminin results in the loss of stem cell identity of ES cells (Yang et al. 2011 ). Blocking
DNA replication in Emi1-depleted cells did not prevent loss of pluripotency indicating
that the effects of geminin on DNA replication and gene transcription are functionally
independent. Indeed, geminin seems to prevent the transcriptional repression of Oct4,
Sox2 and Nanog, three transcriptional activators essential for the pluripotency of embry-
onic ES cells (Yang et al. 2011 ). Thus, subtle changes in the capacity of the APC/C to
target substrate proteins for destruction and altered transcriptional activities allow the
adaption of cell cycle and differentiation events to the specific requirements of the cells
in the ICM and trophoblast.
3.8 Conclusions
The concept of regulating cell cycle progression by alternating activities of Cdk1
and antagonising phosphatases represents the core building block of cell cycle regu-
lation (Fig. 3.7). Yet, within this consensus framework, there is an enormous degree
of plasticity to adjust the timing of cell cycle events to the specific requirement of a
distinct developmental stage, e.g. first mitotic division vs. early embryonic divi-
sions, or developmental fate of embryonic cells, e.g. ICM versus trophoblast cells.
This degree of plasticity is achieved by subtle changes in the impact that the differ-
ent modules have on the activities of Cdk1 and/or phosphatases. As shown for gemi-
nin in mice, equipping an APC/C substrate with two functions, i.e. control of DNA
replication and transcription, enables cells to adjust simultaneously two critical
embryonic processes by changes in the capacity of the APC/C to target proteins for
3 Regulation of Cell Division