Regulation of Cyclin E degradation
The degradation of Cyclin E is crucial during the cell cycle for several reasons. CyclinE, in complex with Cdk2 promotes the transition from the G1 phase to the S phase of the cell cycle, initiating DNA replication. Its timely degradation ensures that cells do not prematurely or inappropriately enter the S phase. Prolonged presence of Cyclin E is observed in many cancer types. Here, uncontrolled S-Phase entry and genomic instability can be involved in oncogenic transformations.
We are interested in the molecular mechanism that regulate Cyclin E degradation during the cell cycle.
Working Model
1) Schematic representation of Drosophila Cyclin E.
NLS: nuclear localization signal, cyclin-box: Interaction domains for Cdk2 binding, p-Degron: Phosphodegron required for Cyclin E degradation
2) An unknown kinase/kinases phosphorylate Cyclin E at the end of G1-phase in the N-terminus
3) The phosphorylated residues provide a docking site for another unknown kinase
4) The kinase can then phosphorylate the C-terminal degron of Cyclin E
5) The phosphorylated phosphodegron can be recognized by an SCF ubiquitin ligase that contains the FBW7(Ago) F-box protein, resulting in Cyclin E ubiquitylation and subsequent degradation in the proteasome
Ongoing projects
Identification and Regulation of the kinase that phoshorylates CyclinE in the N-terminus
Which residues are phosphorylated in the N-terminus?
Identification and Regulation of the docking kinase that binds to the phoshorylated Cyclin E in the N-terminus and that causes phoshorylation of Cyclin E in the C-terminus
Regulation of the FBW7/Ago containing ubiquitin ligase