Securin and not CDK1/cyclin B1 regulates sister chromatid disjunction during meiosis II in mouse eggs

Nabti, Ibtissem; Reis, Alexandra; Levasseur, Mark; Stemmann, Olaf; Jones, Kevin

doi:10.1016/j.ydbio.2008.06.036

Cited by 34 publications

(44 citation statements)

References 47 publications

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“…Cytoplasmic levels of IFY-1-GFP were also reduced immediately after chromosomal IFY-1-GFP degradation and maintained at a low level during meiosis II and the following mitoses. This drastic change in the total cellular level of IFY-1 during meiosis is comparable to securin dynamics in mouse oocytes (Nabti et al, 2008;McGuinness et al, 2009). …”

Section: Dynamic Change In the Subcellular Localization Of Ify-1 Durimentioning

confidence: 56%

HECT-E3 ligase ETC-1 regulates securin and cyclin B1 cytoplasmic abundance to promote timely anaphase during meiosis inC. elegans

et al. 2013

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SUMMARYThe anaphase inhibitor securin plays a crucial role in regulating the timing of sister chromatid separation during mitosis. When sister chromatid pairs become bioriented, the E3 ligase anaphase promoting complex/cyclosome (APC/C) ubiquitylates securin for proteolysis, triggering sister chromatid separation. Securin is also implicated in regulating meiotic progression. Securin protein levels change sharply during cell cycle progression, enabling its timely action. To understand the mechanism underlying the tightly regulated dynamics of securin, we analyzed the subcellular localization of the securin IFY-1 during C. elegans development. IFY-1 was highly expressed in the cytoplasm of germ cells. The cytoplasmic level of IFY-1 declined immediately following meiosis I division and remained low during meiosis II and following mitoses. We identified a C. elegans homolog of another type of E3 ligase, UBE3C, designated ETC-1, as a regulator of the cytoplasmic IFY-1 level. RNAi-mediated depletion of ETC-1 stabilized IFY-1 and CYB-1 (cyclin B1) in post-meiosis I embryos. ETC-1 knockdown in a reduced APC function background caused an embryonic lethal phenotype. In vitro, ETC-1 ubiquitylates IFY-1 and CYB-1 in the presence of the E2 enzyme UBC-18, which functions in pharyngeal development. Genetic analysis revealed that UBC-18 plays a distinct role together with ETC-1 in regulating the cytoplasmic level of IFY-1 during meiosis. Our study reports a novel mechanism, mediated by ETC-1, that co-operates with APC/C to maintain the meiotic arrest required for proper cell cycle timing during reproduction.

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Section: Dynamic Change In the Subcellular Localization Of Ify-1 Durimentioning

confidence: 56%

HECT-E3 ligase ETC-1 regulates securin and cyclin B1 cytoplasmic abundance to promote timely anaphase during meiosis inC. elegans

et al. 2013

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“…Microinjection and Imaging-cDNA was diluted in nucleasefree water to a concentration of 1 g/l prior to microinjection, which was performed on the heated stage of a Nikon TE3000 as described previously (5,43,44). Immunofluorescence was performed on fixed and permeabilized eggs as described previously (44).…”

Section: Methodsmentioning

confidence: 99%

Essential Role of Protein Phosphatase 2A in Metaphase II Arrest and Activation of Mouse Eggs Shown by Okadaic Acid, Dominant Negative Protein Phosphatase 2A, and FTY720

Chang¹,

Jennings

Stewart

et al. 2011

Journal of Biological Chemistry

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Vertebrate eggs arrest at second meiotic metaphase. The fertilizing sperm causes meiotic exit through Ca 2؉ -mediated activation of the anaphase-promoting complex/cyclosome (APC/ C). Although the loss in activity of the M-phase kinase CDK1 is known to be an essential downstream event of this process, the contribution of phosphatases to arrest and meiotic resumption is less apparent, especially in mammals. Therefore, we explored the role of protein phosphatase 2A (PP2A) in mouse eggs using pharmacological inhibition and activation as well as a functionally dominant-negative catalytic PP2A subunit (dn-PP2Ac-L199P) coupled with live cell imaging. We observed that PP2A inhibition using okadaic acid induced events normally observed at fertilization: degradation of the APC/C substrates cyclin B1 and securin resulting from loss of the APC/C inhibitor Emi2. Although sister chromatids separated, chromatin remained condensed, and polar body extrusion was blocked as a result of a rapid spindle disruption, which could be ameliorated by nondegradable cyclin B1, suggesting that spindle integrity was affected by CDK1 loss. Similar cell cycle effects to okadaic acid were also observed using dominant-negative PP2Ac. Preincubation of eggs with the PP2A activator FTY720 could block many of the actions of okadaic acid, including Emi2, cyclin B1, and securin degradation and sister chromatid separation. Therefore, in conclusion, we used okadaic acid, dn-PP2Ac-L199P, and FTY720 on mouse eggs to demonstrate that PP2A is needed to for both continued metaphase arrest and successful exit from meiosis.Mouse eggs, as with most vertebrates, arrest at metaphase of the second meiotic division (metII) 3 until fertilized (1-3). Crucial to this arrest is inhibition of the anaphase-promoting complex/cyclosome (APC/C), thereby preventing cyclin B1 and securin degradation and so maintaining high CDK1 kinase (also known as Maturation Promoting Factor, MPF; CDK1/cyclin B1) and low separase (ESPL1) protease activities, respectively (1, 4 -6). At fertilization, a sperm-derived Ca 2ϩ signal causes loss of the APC/C inhibitor Emi2, resulting in a drop in CDK1 activity by cyclin B1 degradation and associated anaphase, driven by the protease separase (7-10).For successful exit from metaphase in either mitosis or meiosis, it is now becoming clear that phosphatase activity is needed to dephosphorylate CDK1 substrates. In Xenopus eggs, calcineurin activity is essential in the process of exit from metII arrest, but this function is not conserved in mouse eggs (11-13). Mammalian eggs may deviate or differ from Xenopus, so it is not always possible to extrapolate across species with accuracy, and indeed this lack of conservation is observed in more than one aspect of cell cycle control (13-15). Instead, the exit of the mouse egg from metII arrest may more closely match mitotic exit in somatic cells and so rely on phosphatase activity from a member of the protein phosphatase 2A (PP2A) family (16 -20).The heterotrimeric nature of the PP2A holoenzyme, coupled with a...

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“…Fertilization causes Emi2/Erp1 degradation, resulting in an acceleration of cyclin B1 degradation (Nixon et al, 2002); lowered Cdk1 activity and meiotic exit also requires Wee1B (Wee2) activity, which is an inhibitory kinase of Cdk1 (Oh et al, 2011). During the time of met II arrest, inhibition of separase is bought about by binding its chaperone securin, and the rise in APC activity at fertilization therefore frees separase by causing the degradation of securin (Nabti et al, 2008).…”

Section: Controlling Meiotic Fidelity In MIImentioning

confidence: 99%

Molecular causes of aneuploidy in mammalian eggs

2013

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SummaryMammalian oocytes are particularly error prone in segregating their chromosomes during their two meiotic divisions. This results in the creation of an embryo that has inherited the wrong number of chromosomes: it is aneuploid. The incidence of aneuploidy rises significantly with maternal age and so there is much interest in understanding this association and the underlying causes of aneuploidy. The spindle assembly checkpoint, a surveillance mechanism that operates in all cells to prevent chromosome mis-segregation, and the cohesive ties that hold those chromosomes together, have thus both been the subject of intensive investigation in oocytes. It is possible that a lowered sensitivity of the spindle assembly checkpoint to certain types of chromosome attachment error may endow oocytes with an innate susceptibility to aneuploidy, which is made worse by an age-related loss in the factors that hold the chromosomes together.

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Securin and not CDK1/cyclin B1 regulates sister chromatid disjunction during meiosis II in mouse eggs

Cited by 34 publications

References 47 publications

HECT-E3 ligase ETC-1 regulates securin and cyclin B1 cytoplasmic abundance to promote timely anaphase during meiosis inC. elegans

HECT-E3 ligase ETC-1 regulates securin and cyclin B1 cytoplasmic abundance to promote timely anaphase during meiosis inC. elegans

Essential Role of Protein Phosphatase 2A in Metaphase II Arrest and Activation of Mouse Eggs Shown by Okadaic Acid, Dominant Negative Protein Phosphatase 2A, and FTY720

Molecular causes of aneuploidy in mammalian eggs

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