Why Cdc2 does not compensate for Cdk2 in late embryogenesis?
The late embryonic lethality of DKOs suggest that Cdk2 and Cdk4 are required to regulate the Rb/E2F pathway only late in development. In agreement with this, cell proliferation in early embryogenesis is comparable in DKO and wild type embryos. Our analysis has shown that Rb phosphorylation decreases progressively after E13.5, and we can only speculate how Rb phosphorylation is maintained in early development. Therefore, we propose four possible models that are not mutually exclusive and can possibly explain our findings (Figure 1). The first possibility (Figure 1B) could be that in early embryogenesis, stem cell and early progenitor cell proliferation is not controlled by Rb and other pocket proteins (p107, p130). It has been shown that proliferation of embryonic stem (ES) cells is not affected by concomitant ablation of all three pocket proteins, whereas similar mutant MEFs proliferate faster than wild type MEFs and loose G1 control [8,9]. On the other hand, Rb appears to be immediate
