PIP degron-stabilized Dacapo/p21Cip1 and mutations inagoact in an anti- versus pro-proliferative manner, yet both trigger an increase in Cyclin E levels

During cell cycle progression, the activity of the CycE-Cdk2 complex gates S-phase entry. CycE-Cdk2 is inhibited by CDK inhibitors (CKIs) of the Cip/Kip family, which include the human p21 Cip1 and Drosophila Dacapo (Dap) proteins. Both the CycE and Cip/Kip family proteins are under elaborate control via protein degradation, mediated by the Cullin-RING ligase (CRL) family of ubiquitin ligase complexes. The CRL complex SCF Fbxw7/Ago argets phosphorylated CycE, whereas p21 Cip1 and Dap are targeted by the CRL4 Cdt2 complex, binding to the PIP degron. The role of CRL-mediated degradation of CycE and Cip/Kip proteins during CNS development is not well understood. Here, we analyse the role of ago ( Fbxw7 )-mediated CycE degradation, and of Dap and p21 Cip1 degradation during Drosophila CNS development. We find tha ago mutants display over-proliferation, accompanied by elevated CycE expression levels. By contrast, expression of PIP degron mutant Dap and p21 Cip1 ransgenes inhibit proliferation. However, surprisingly, this is also accompanied by elevated CycE levels. Hence, ago mutation and PIP degron Cip/Kip transgenic expression trigger opposite effects on proliferation, but similar effects on CycE levels.