The role of p57Kip2 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, APCCdh1 will be assembled instead of APCCdc20. 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, APCCdh1 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, APCCdh1/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  suggesting that APCCdh1/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 . In cells programmed for endoreduplication, inhibition of Cdk1 activity results in premature assembly of APCCdh1/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.