A role for Cdc2- and PP2A-mediated regulation of Emi2 in the maintenance of CSF arrest.
BACKGROUND: Vertebrate oocytes are arrested in metaphase II of meiosis prior to fertilization by cytostatic factor (CSF). CSF enforces a cell-cycle arrest by inhibiting the anaphase-promoting complex (APC), an E3 ubiquitin ligase that targets Cyclin B for degradation. Although Cyclin B synthesis is ongoing during CSF arrest, constant Cyclin B levels are maintained. To achieve this, oocytes allow continuous slow Cyclin B degradation, without eliminating the bulk of Cyclin B, which would induce release from CSF arrest. However, the mechanism that controls this continuous degradation is not understood. RESULTS: We report here the molecular details of a negative feedback loop wherein Cyclin B promotes its own destruction through Cdc2/Cyclin B-mediated phosphorylation and inhibition of the APC inhibitor Emi2. Emi2 bound to the core APC, and this binding was disrupted by Cdc2/Cyclin B, without affecting Emi2 protein stability. Cdc2-mediated phosphorylation of Emi2 was antagonized by PP2A, which could bind to Emi2 and promote Emi2-APC interactions. CONCLUSIONS: Constant Cyclin B levels are maintained during a CSF arrest through the regulation of Emi2 activity. A balance between Cdc2 and PP2A controls Emi2 phosphorylation, which in turn controls the ability of Emi2 to bind to and inhibit the APC. This balance allows proper maintenance of Cyclin B levels and Cdc2 kinase activity during CSF arrest.
Pubmed ID: 17276914 RIS Download
Anaphase-Promoting Complex-Cyclosome | Animals | CDC2 Protein Kinase | Cdc20 Proteins | Cell Cycle Proteins | Cyclin B | DNA, Complementary | Enzyme Inhibitors | F-Box Proteins | Gene Library | Humans | Meiosis | Okadaic Acid | Oocytes | Phosphoprotein Phosphatases | Phosphorylation | Protein Binding | Proto-Oncogene Proteins c-mos | Recombinant Fusion Proteins | Ubiquitin-Protein Ligase Complexes | Xenopus | Xenopus Proteins