Article

A role for Cdc2- and PP2A-mediated regulation of Emi2 in the maintenance of CSF arrest.

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Current Biology (Impact Factor: 9.49). 03/2007; 17(3):213-24. DOI:10.1016/j.cub.2006.12.045
Source: PubMed

ABSTRACT 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.
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.
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.

0 0
 · 
1 Bookmark
 · 
74 Views
  • Source
    04/2012; , ISBN: 978-953-51-0466-7
  • [show abstract] [hide abstract]
    ABSTRACT: Mitotic divisions result from the oscillating activity of cyclin-dependent kinase-1 (Cdk1). Cdk1 activity is terminated by the anaphase-promoting-complex/cyclosome (APC/C), a ubiquitin-ligase that targets cyclin-B for destruction. In somatic divisions, Emi1 and the spindle-assembly-checkpoint (SAC) regulate cell-cycle progression by inhibiting the APC/C. Early embryonic divisions lack these APC/C-inhibitory components, raising the question of how these cycles are controlled. Here, we found that the APC/C-inhibitory activity of XErp1/Emi2 was essential for early divisions in Xenopus embryos. Loss of XErp1 resulted in untimely destruction of APC/C-substrates and embryonic lethality. XErp1's APC/C-inhibitory function was negatively regulated by Cdk1 and positively by protein-phosphatase-2A (PP2A). Thus, Cdk1 and PP2A are at the core of early mitotic cell-cycles by antagonistically controlling XErp1-activity resulting in oscillating APC/C activity.
    Science 09/2012; · 31.20 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Egg activation is the final transition that an oocyte goes through to become a developmentally competent egg. This transition is usually triggered by a calcium-based signal that is often, but not always, initiated by fertilization. Activation encompasses a number of changes within the egg. These include changes to the egg's membranes and outer coverings to prevent polyspermy and to support the developing embryo, as well as resumption and completion of the meiotic cell cycle, mRNA polyadenylation, translation of new proteins, and the degradation of specific maternal mRNAs and proteins. The transition from an arrested, highly differentiated cell, the oocyte, to a developmentally active, totipotent cell, the activated egg or embryo, represents a complete change in cellular state. This is accomplished by altering ion concentrations and by widespread changes in both the proteome and the suite of mRNAs present in the cell. Here, we review the role of calcium and zinc in the events of egg activation, and the importance of macromolecular changes during this transition. The latter include the degradation and translation of proteins, protein posttranslational regulation through phosphorylation, and the degradation, of maternal mRNAs.
    Current Topics in Developmental Biology 01/2013; 102:267-92. · 6.91 Impact Factor

Full-text (2 Sources)

View
12 Downloads
Available from
Aug 29, 2013