The Cdc25 family of protein phosphatases positively regulate the cell division cycle by activating cyclin-dependent protein kinases. In humans and rodents, three Cdc25 family members denoted Cdc25A, -B, and -C have been identified.
Prophase I arrest and progression to metaphase I in mouse oocytes: Comparison of resumption of meiosis and recovery from G2-arrest in somatic cells. Solc P et al. Mammalian oocytes are arrested at prophase I until puberty when luteinizing hormone (LH) induces resumption of meiosis of follicle-enclosed oocytes. Resumption of meiosis is tightly coupled with regulating cyclin dependant kinase 1 (CDK1) activity. Prophase I arrest depends on inhibitory phosphorylation of CDK1 and anaphase-promoting complex - (APC-CDH1)-mediated regulation of cyclin B levels. Prophase I arrest is maintained by endogenously produced cAMP, which activates protein kinase A (PKA) that in turn phosphorylates (and activates) the nuclear kinase WEE2. In addition, PKA-mediated phosphorylation of the phosphatase CDC25B results in its cytoplasmic retention. The combined effect maintains low levels of CDK1 activity that are not sufficient to initiate resumption of meiosis. LH triggers synthesis of epidermal growth factor (EGF)-like factors in mural granulosa cells and leads to reduced cGMP transfer from cumulus cells to oocytes via gap junctions that couple the two cell types. cGMP inhibits oocyte phosphodiesterase 3A (PDE3A) and a decline in oocyte cGMP results in increased PDE3A activity. The ensuing decrease in oocyte cAMP triggers maturation by alleviating the aforementioned phosphorylations of WEE2 and CDC25B. As a direct consequence CDC25B translocates into the nucleus. The resulting activation of CDK1 also promotes extrusion of WEE2 from the nucleus thereby providing a positive amplification mechanism for CDK1 activation. Other kinases, e.g., protein kinase B (PKB), Aurora kinase A (AURKA) and polo-like kinase 1 (PLK1), also participate in resumption of meiosis. Mechanisms governing meiotic prophase I arrest and resumption of meiosis share common features with DNA damage-induced mitotic G2 checkpoint arrest and checkpoint recovery, respectively. These common features include CDC14B-dependent activation of APC-CDH1 in prophase I arrested oocytes or G2 arrested somatic cells, and CDC25B-dependent cell cycle resumption in both oocytes and somatic cells. Oocyte maturation arrest at GV stage
NCBI Summary:
CDC25B is a member of the CDC25 family of phosphatases. CDC25B activates the cyclin dependent kinase CDC2 by removing two phosphate groups and it is required for entry into mitosis. CDC25B shuttles between the nucleus and the cytoplasm due to nuclear localization and nuclear export signals. The protein is nuclear in the M and G1 phases of the cell cycle and moves to the cytoplasm during S and G2. CDC25B has oncogenic properties, although its role in tumor formation has not been determined. Multiple transcript variants for this gene exist. [provided by RefSeq, Jul 2008]
General function
Cell cycle regulation, Enzyme
Comment
14-3-3 epsilon prevents G2/M transition of fertilized mouse eggs by binding with CDC25B. Cui C 2014 et al.
BackgroundThe 14-3-3 (YWHA) proteins are highly conserved in higher eukaryotes, participate in various cellular signaling pathways including cell cycle regulation, development and growth. Our previous studies demonstrated that 14-3-3 (YWHAE) is responsible for maintaining prophase | arrest in mouse oocyte. However, roles of 14-3-3 in the mitosis of fertilized mouse eggs have remained unclear. Here, we showed that 14-3-3 interacts and cooperates with CDC25B phosphorylated at Ser321 regulating G2/M transition of mitotic progress of fertilized mouse eggs.ResultsDisruption of 14-3-3 expression by RNAi prevented normal G2/M transition by inhibition of MPF activity and leaded to the translocation of CDC25B into the nucleus from the cytoplasm. Overexpression of 14-3-3-WT and unphosphorylatable CDC25B mutant (CDC25B-S321A) induced mitotic resumption in dbcAMP-arrested eggs. In addition, we examined endogenous and exogenous distribution of 14-3-3 and CDC25B. Endogenous 14-3-3 and CDC25B were co-localized primarily in the cytoplasm at the G1, S, early G2 and M phases whereas CDC25B was found to accumulate in the nucleus at the late G2 phase. Upon coexpression with RFP14-3-3, GFPCDC25BWT and GFPCDC25BS321A were predominantly cytoplasmic at early G2 phase and then GFPCDC25BS321A moved to the nucleus whereas CDC25B-WT signals were observed in the cytoplasm without nucleus accumulation at late G2 phase at presence of dbcAMP.ConclusionsOur data indicate that 14-3-3 is required for the mitotic entry in the fertilized mouse eggs. 14-3-3 is primarily responsible for sequestering the CDC25B in cytoplasm and 14-3-3 binding to CDC25B-S321 phosphorylated by PKA induces mitotic arrest at one-cell stage by inactivation of MPF in fertilized mouse eggs.
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Protein kinase a modulates Cdc25B activity during meiotic resumption of mouse oocytes. Zhang Y et al. Protein kinase A (PKA) play a critical role in maintaining the meiotic arrest. However, the steps downstream of PKA remain largely unknown. In this study, we investigated the regulation of meiotic resumption by PKA/Cdc25B pathway in mouse oocytes. Injection of mRNA coding for Cdc25b-S321A had a more potent maturation-inducing ability than Cdc25b-WT. When co-injected with PKA inhibitor, Cdc25B-WT had similar activities with Cdc25B-S321A. Meanwhile, the phosphorylation of Cdc25B-S321 was detected in germinal vesicle (GV) oocytes by Western blotting with a phospho-Ser321-specific antibody and the band disappeared when oocytes reenter into the meiotic cell cycle. Furthermore, Cdc25B-WT translocated to the nucleus shortly before GV breakdown (GVBD), whereas phosphorylated Cdc25B-S321 expressed exclusively in the cytoplasm and the signal could not be detected in GVBD oocytes. Taken together, these data indicate that Cdc25B-Serine321 is the potential PKA target and Cdc25B subcellular localization determines its function during the process of maintaining GV arrest in mouse oocytes. Developmental Dynamics 237:3777-3786, 2008. (c) 2008 Wiley-Liss, Inc.
Ovarian localization
Oocyte
Comment
The Role of 14-3-3e Interaction with Phosphorylated Cdc25B at Its Ser321 in the Release of the Mouse Oocyte from Prophase I Arrest. Meng J et al. The protein kinase A (PKA)/Cdc25B pathway plays a critical role in maintaining meiotic arrest in mouse oocytes. However, the molecular mechanism underlying this interchange is not known. In this study, we assessed the role of 14-3-3e interaction with phosphorylated Cdc25B at its Ser321 as the mouse oocyte is released from prophase I arrest. The 14-3-3e isoform is a highly conserved protein with various regulatory roles, including maintenance of meiotic arrest. Cdc25B phosphatase is also a key cell cycle regulator. 14-3-3e binds to Cdc25B-WT, which was abrogated when Ser321 of Cdc25B was mutated to Ala. In addition, we found that 14-3-3e and Cdc25B were co-localized. Cdc25B was translocated from the cytoplasm to the nucleus shortly before germinal vesicle breakdown (GVBD) during the primary oocyte stage of oogenesis. However, mutation of Ser321 to Ala completely abolished the cytoplasmic localization of Cdc25B. Furthermore, oocytes co-expressing of Cdc25B-WT or Cdc25B-Ser321D and 14-3-3e were unable to undergo GVBD. In contrast, co-expression of 14-3-3e and Cdc25B-Ser321A induced GVBD and allowed the process to continue. Down-regulation of 14-3-3e caused partial meiotic resumption. Taken together, these data indicate that Ser321 of Cdc25B is the specific binding site for 14-3-3e binding, and that 14-3-3e is the significant factor in Cdc25B regulation during meiotic resumption of GV stage.
Follicle stages
Primary, Secondary, Antral, Preovulatory
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:Lincoln AJ, 2002 et al reported that Cdc25b phosphatase is required for resumption of meiosis during
oocyte maturation.
In a wide variety of animal species, oocyte
maturation is arrested temporarily at
prophase of meiosis I . Resumption of
meiosis requires activation of
cyclin-dependent kinase-1 (CDK1, p34cdc2),
one component of maturation-promoting
factor (MPF). The dual specificity
phosphatases Cdc25a, Cdc25b and Cdc25c
are activators of cyclin-dependent kinases4-8;
consequently, they are postulated to regulate
cell-cycle progression in meiosis and mitosis
as well as the DNA-damage response9-12. The authors
generated Cdc25b-deficient (Cdc25b-/-) mice
and found that they are viable. As compared
with wildtype cells, fibroblasts from Cdc25b-/-
mice grew vigorously in culture and arrested
normally in response to DNA damage. Female
Cdc25b-/- mice were sterile, and Cdc25b-/-
oocytes remained arrested at prophase with
low MPF activity. Microinjection of wildtype
Cdc25b mRNA into Cdc25b-/- oocytes caused
activation of MPF and resumption of meiosis.
Thus, Cdc25b-/- female mice are sterile
because of permanent meiotic arrest resulting
from the inability to activate MPF. Cdc25b is
therefore essential for meiotic resumption in
female mice. Mice lacking Cdc25b provide the
first genetic model for studying the
mechanisms regulating prophase arrest in
vertebrates.