Figure 4

The role of p57^Kip2 in the initiation and maintenance of endocycles. (A) Endocycles are initiated in mouse TS cells in the absence of FGF4. When p57 is expressed in TS cells as a consequence of FGF4 deprivation, Cdk1 activity is inhibited. Consequently, APC^Cdh1 will be assembled instead of APC^Cdc20. Orc1 will not be phosphorylated. In the absence of phosphorylation, any Orc1-P and Cdc6-P produced during S and G2-phases by Cdk2:CcnA will be dephosphorylated by cellular protein phosphatases. In the absence of CDK activity, APC^Cdh1 is assembled and targets geminin for degradation. Thus, the cell has effectively entered a G1-phase-like state without passing through mitosis. (B) Based on studies of endocycles in Drosophila follicle cells, Cdk2:cyclin E activity oscillates such that it is high during the S-phases and low during the G-phases. In contrast, APC^Cdh1/Fzr activity is high during G-phases and low during S-phases [40, 41]. This is in keeping with the fact that Cyclin E:Cdk2 inactivates Cdh1/Fzr [51] suggesting that APC^Cdh1/Fzr oscillations are driven by periodic inhibition of Fzr by Cyclin E:Cdk2 [40, 41]. Similarly, geminin levels are high during S-phase and low during gap phase [41]. In cells programmed for endoreduplication, inhibition of Cdk1 activity results in premature assembly of APC^Cdh1/Fzr. Thus, a feedback loop exists that reinforces inhibition of Cdk1 activity triggered by endocycle entry. In the absence of Geminin and CDK-dependent protein phosphorylation, preRC assembly occurs as though cells had entered G1-phase. Symbols: ⊥ indicates target is inhibited, +→ indicates target is activated, → indicates product of reaction.