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cell division cycle 25B OKDB#: 1470
 Symbols: CDC25B Species: human
 Synonyms:  Locus: 20p13 in Homo sapiens


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General Comment 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. /////////////////////////
Cellular localization Cytoplasmic, Nuclear
Comment
Ovarian function Oogenesis, Oocyte maturation , Germinal vesicle breakdown
Comment YWHA (14-3-3) protein isoforms and their interactions with CDC25B phosphatase in mouse oogenesis and oocyte maturation. Eisa AA et al. (2019) Immature mammalian oocytes are held arrested at prophase I of meiosis by an inhibitory phosphorylation of cyclin-dependent kinase 1 (CDK1). Release from this meiotic arrest and germinal vesicle breakdown is dependent on dephosphorylation of CDK1 by the protein, cell cycle division 25B (CDC25B). Evidence suggests that phosphorylated CDC25B is bound to YWHA (14-3-3) proteins in the cytoplasm of immature oocytes and is thus maintained in an inactive form. The importance of YWHA in meiosis demands additional studies. Messenger RNA for multiple isoforms of the YWHA protein family was detected in mouse oocytes and eggs. All seven mammalian YWHA isoforms previously reported to be expressed in mouse oocytes, were found to interact with CDC25B as evidenced by in situ proximity ligation assays. Interaction of YWHAH with CDC25B was indicated by Förster Resonance Energy Transfer (FRET) microscopy. Intracytoplasmic microinjection of oocytes with R18, a known, synthetic, non-isoform-specific, YWHA-blocking peptide promoted germinal vesicle breakdown. This suggests that inhibiting the interactions between YWHA proteins and their binding partners releases the oocyte from meiotic arrest. Microinjection of isoform-specific, translation-blocking morpholino oligonucleotides to knockdown or downregulate YWHA protein synthesis in oocytes suggested a role for a specific YWHA isoform in maintaining the meiotic arrest. More definitively however, and in contrast to the knockdown experiments, oocyte-specific and global deletion of two isoforms of YWHA, YWHAH (14-3-3 eta) or YWHAE (14-3-3 epsilon) indicated that the complete absence of either or both isoforms does not alter oocyte development and release from the meiotic prophase I arrest. Multiple isoforms of the YWHA protein are expressed in mouse oocytes and eggs and interact with the cell cycle protein CDC25B, but YWHAH and YWHAE isoforms are not essential for normal mouse oocyte maturation, fertilization and early embryonic development.////////////////// Successive recruitment of p-CDC25B-Ser351 and p-cyclin B1-Ser123 to centrosomes contributes to the release of mouse oocytes from prophase I arrest. Zhao X et al. (2014) Background: The molecular mechanism that controls the activation of Cyclin B1-CDK1 complex has been widely investigated. It is generally believed that CDC25B acts as a "starter phosphatase" of mitosis. In this study, we investigate the sequential regulation of meiotic resumption by CDC25B and Cyclin B1 in mouse oocytes. Results: Injection of mRNAs coding for CDC25B-Ser351A and/or Cyclin B1-Ser123A shows a more potent maturation-inhibiting ability than their respective wild type. Co-injection of mRNAs coding for phosphor-mimic CDC25B-Ser351D and Cyclin B1-Ser123D can rescue this prophase I arrest induced by CDC25B-Ser351A or Cyclin B1-Ser123A. In addition, p-CDC25B-Ser351 is co-localized at the microtubule-organizing centers (MTOCs) with Aurora kinase A (AURKA) during maturation and p-Cyclin B1-Ser123 is only captured on MTOCs shortly before germinal vesicle breakdown (GVBD). Depletion of AURKA not only resulted in metaphase I (MI) spindle defects and anaphase I (AI) abnormal chromosomes separation but also prevented the phosphorylation of CDC25B-Ser351 at centrosomes. AURKA depletion induced deficiencies of spindle assembly and progression to MII can be rescued by CDC25B-Ser351D mRNA injection. Conclusions: AURKA induced phosphorylation and recruitment of CDC25B to MTOCs prior to p-Cyclin B1-Ser123, and this sequential regulation is essential for the commitment of the oocytes to resume meiosis. Developmental Dynamics, 2014. © 2014 Wiley Periodicals, Inc.////////////////// Cdc25B phosphatase participates in maintaining metaphase II arrest in mouse oocytes. Kang H et al. Cdc25B is an essential regulator for meiotic resumption in mouse oocytes. However, the role of this phosphatase during the later stage of the meiotic cell cycle is not known. In this study, we investigated the role of Cdc25B during metaphase II (MII) arrest in mouse oocytes. Cdc25B was extensively phosphorylated during MII arrest with an increase in the phosphatase activity toward Cdk1. Downregulation of Cdc25B by antibody injection induced the formation of a pronucleus-like structure. Conversely, overexpression of Cdc25B inhibited Ca(2+)-mediated release from MII arrest. Moreover, Cdc25B was immediately dephosphorylated and hence inactivated during MII exit, suggesting that Cdk1 phosphorylation is required to exit from MII arrest. Interestingly, this inactivation occurred prior to cyclin B degradation. Taken together, our data demonstrate that MII arrest in mouse oocytes is tightly regulated not only by the proteolytic degradation of cyclin B but also by dynamic phosphorylation of Cdk1.////////////// Cytoplasmic polyadenylation controls cdc25B mRNA translation in rat oocytes resuming meiosis. Gershon E et al. Resumption of meiosis in oocytes represents the entry into M-phase of the cell cycle and is regulated by the maturation-promoting factor (MPF). Activation of MPF is catalyzed by the dual specificity phosphatase, cdc25. In mammals, cdc25 is represented by a multigene family consisting of three isoforms: A, B and C. A recent report that female mice lacking cdc25B exhibit impaired fertility suggests a role for this isoform in regulating the G2- to M-transition in mammalian oocytes. Supporting the above-mentioned observation, we demonstrate herein that microinjection of neutralizing antibodies against cdc25B interfered with the ability of rat oocytes to undergo germinal vesicle breakdown (GVB). We also show accumulation of cdc25B in GVB oocytes and a transient reduction in its amount at metaphase I of meiosis. The accumulation of cdc25B was associated with its mRNA cytoplasmatic polyadenylation and was prevented by the protein synthesis inhibitor cyclohexamide as well as by the polyadenylation inhibitor cordycepin. Immunofluorescence staining revealed translocation of cdc25B to the metaphase II spindle apparatus. Taken together, our findings provide evidence that cdc25B is involved in resumption of meiosis in rat oocytes. We further demonstrate for the first time, a periodic accumulation of cdc25B throughout meiosis that is translationally regulated and involves cdc25B mRNA polyadenylation.
Expression regulated by
Comment 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.

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Phenotypes and GWAS show phenotypes and GWAS
Links
OMIM (Online Mendelian Inheritance in Man: an excellent source of general gene description and genetic information.)
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created: April 3, 2002, 1:59 p.m. by: hsueh   email:
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last update: Oct. 30, 2019, 2:01 p.m. by: hsueh    email:



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