Affinage

CDC25A

M-phase inducer phosphatase 1 · UniProt P30304

Length
524 aa
Mass
59.1 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC25A is a dual-specificity phosphatase that drives cell-cycle progression by dephosphorylating and activating cyclin-dependent kinase complexes at successive transitions: it binds cyclin E/A-CDK2 through an N-terminal cyclin-binding (Cy) motif and removes inhibitory phosphorylation to license S-phase entry (PMID:9234691), dephosphorylates CDK1/Cdc2 to permit the G2/M transition (PMID:12676925), and binds and activates cyclin B-CDK1 during mitosis (PMID:12411508). Its catalysis proceeds through a dissociative transition state, with glutamate 431 essential for hydrolysis of high-leaving-group substrates (PMID:11805096). The dominant layer of control over CDC25A is regulated proteolysis: in response to DNA damage or during unperturbed S phase, the ATR-Claspin-Rad9-Hus1 axis activates Chk1 (PMID:15190204), which—together with Chk2 after ionizing radiation (PMID:11298456)—triggers ubiquitin-proteasome destruction of CDC25A to enforce the S-phase and G2/M checkpoints and block radioresistant DNA synthesis (PMID:10827953, PMID:30635443). Degradation is executed by the SCF-β-TrCP E3 ligase, which recognizes a noncanonical phosphodegron built hierarchically: Chk1 (and GSK-3β) phosphorylate the priming Ser76, enabling CK1α phosphorylation of Ser79/Ser82 for β-TrCP binding (PMID:14681206, PMID:20348946, PMID:18480045), with additional kinases (NEK11, activated by Chk1; GSK-3β primed by Plk3; p90RSK/ERK; STK38; CDK4/6; DYRK2) feeding into this destruction program (PMID:19734889, PMID:18167338, PMID:19244340, PMID:28192398, PMID:25936524). Opposing degradation, the deubiquitylases Dub3 and USP7 (recruited by BRE/BRCC45) stabilize CDC25A (PMID:20228808, PMID:29416040). Transcriptionally, CDC25A is induced through an E2F site relieved of p107/p130 repression by serum (PMID:10373518) and is repressed by p53 acting indirectly via ATF3 (PMID:17001315, PMID:19060337) and by TGF-β (PMID:9163429). Beyond cell-cycle CDKs, CDC25A dephosphorylates additional substrates that extend its reach into mitogenic and metabolic signaling—EGFR and ERK (PMID:11912208, PMID:15672448), nuclear PKM2 to promote the Warburg effect (PMID:27485204), and TBK1 at Ser172 to dampen RIG-I antiviral interferon signaling (PMID:30021902).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 High

    Established that genotoxic stress eliminates CDC25A through regulated proteolysis rather than transcriptional shutdown, defining the molecular basis of the S-phase checkpoint.

    Evidence Proteasome inhibition and Chk1 inhibition during UV/IR in cultured cells, with overexpression bypassing the checkpoint

    PMID:10827953

    Open questions at the time
    • Did not identify the E3 ligase or the phosphodegron
    • p53-independence shown but upstream kinase cascade not yet resolved
  2. 2001 High

    Resolved the upstream checkpoint kinases for IR, showing ATM and Chk2 phosphorylate CDC25A on Ser123 to halt replication, placing CDC25A as the effector of the radioresistant-DNA-synthesis checkpoint.

    Evidence ATM/Chk2 mutant cells, in vitro Chk2 phosphorylation of S123, dominant-negative Chk2, and CDK2-AF rescue

    PMID:11298456

    Open questions at the time
    • Relationship between Chk2/S123 and the later-defined Chk1/Ser76 degron unresolved
    • Did not reconstitute ubiquitination
  3. 2002 High

    Defined the substrate-recognition and catalytic basis of CDC25A activity—an N-terminal Cy motif for cyclin-CDK2 engagement and a dissociative catalytic mechanism with E431—and showed mitotic stabilization couples it to cyclin B-CDK1.

    Evidence Mutant binding/co-IP and Xenopus extract reconstitution (Cy motif); kinetic isotope effects and Brønsted analysis (catalysis); MS phosphosite mapping and RNAi (mitotic role)

    PMID:11805096 PMID:12411508 PMID:9234691

    Open questions at the time
    • Structural model of phosphodegron-β-TrCP interaction not addressed
    • How Cy-motif selectivity is regulated across cell cycle unclear
  4. 2003 High

    Identified SCF-β-TrCP as the direct E3 ligase and mapped the noncanonical Ser79/Ser82 phosphodegron primed at Ser76 by Chk1, mechanistically completing the degradation pathway and extending CDC25A control to the G2/M transition.

    Evidence In vitro ubiquitination reconstitution, β-TrCP siRNA with radioresistant DNA synthesis, phosphodegron mutagenesis, and Chk1 siRNA with CDK1 dephosphorylation assays

    PMID:12676925 PMID:14603323 PMID:14681206

    Open questions at the time
    • Did not enumerate all priming kinases feeding Ser76
    • Counteracting deubiquitylation not yet defined
  5. 2004 Medium

    Demonstrated the Chk1-CDC25A circuit operates during unperturbed S phase under ATR/Claspin/Rad9/Hus1 control, not only after exogenous damage, defining a physiological surveillance role.

    Evidence Chemical/genetic ATR ablation and siRNA of Claspin, Rad9, Hus1 with CDC25A and Chk1-S345 immunoblotting

    PMID:15190204

    Open questions at the time
    • Quantitative contribution of each component not separated
    • Link to replication origin firing not addressed
  6. 2008 High

    Expanded the kinase network priming the degron (GSK-3β via Plk3; CK1α building Ser79/82 hierarchically on Ser76) and showed Chk1, not Chk2, is the principal Ser76 kinase for damage-induced degradation, with a parallel transcriptional arm via p53-ATF3.

    Evidence In vitro kinase reconstitutions, hierarchical phosphorylation, isogenic CHK2-/- cells with Chk1 siRNA epistasis, and ATF3 ChIP on the CDC25A promoter

    PMID:18167338 PMID:18480045 PMID:19060337 PMID:20348946

    Open questions at the time
    • Spatiotemporal coordination of the multi-kinase cascade not resolved
    • p53 represses without direct promoter binding, exact bridging factor beyond ATF3 unclear
  7. 2009 High

    Identified NEK11 as a Chk1-activated kinase that directly phosphorylates CDC25A to enable β-TrCP-mediated ubiquitylation, and showed ERK/p90RSK can route CDC25A to the same degradation machinery, broadening checkpoint and mitogenic inputs.

    Evidence shRNA screen, in vitro Chk1->NEK11->CDC25A phosphorylation cascade, β-TrCP ubiquitylation assays; Xenopus p90RSK/ERK phosphorylation and reconstituted degradation

    PMID:19244340 PMID:19734889

    Open questions at the time
    • Relative dominance of NEK11 vs direct Chk1 phosphorylation in vivo unclear
    • p90RSK route shown in Xenopus, mammalian contribution not quantified
  8. 2010 High

    Defined the deubiquitylation arm and the scaffolded checkpoint complex—Dub3 reverses CDC25A polyubiquitylation, while a 14-3-3γ/Chk1(pS296)/CDC25A ternary complex couples Chk1 autophosphorylation to CDC25A degradation.

    Evidence Co-IP, ubiquitylation assays, Dub3 siRNA with cell-cycle arrest and xenograft validation; phospho-specific antibodies and Chk1-S296A rescue for the ternary complex

    PMID:20228808 PMID:20639859

    Open questions at the time
    • How Dub3 activity is itself regulated unknown
    • Whether USP7 and Dub3 act on distinct ubiquitin pools unresolved
  9. 2018 High

    Extended CDC25A substrate repertoire beyond CDKs to innate immunity, showing it dephosphorylates TBK1-S172 to suppress IRF3 activation and IFN-β, and identified BRE/USP7 as a stabilizing module relevant to BRCA2-deficient survival.

    Evidence In vitro dephosphorylation of TBK1-S172, co-IP, siRNA, IFN-β reporters and viral infection; insertional mutagenesis screen and BRE-USP7-CDC25A co-IP

    PMID:29416040 PMID:30021902

    Open questions at the time
    • Physiological conditions selecting TBK1 vs CDK substrates unclear
    • How BRE/USP7 recruitment is signaled not defined
  10. 2021 Medium

    Identified DYRK2 as an E3-ligase-independent route to CDC25A degradation forming a mutual feedback loop, and confirmed via endogenous-degron epistasis that Chk1's main role in normal cycling is to limit CDC25A.

    Evidence In vitro DYRK2 kinase and phosphosite mapping with proteasomal degradation assays; CRISPR/auxin-degron Chk1 depletion with Chk1+CDC25A double-depletion epistasis

    PMID:30635443 PMID:34363019

    Open questions at the time
    • E3 ligase mediating DYRK2-driven degradation not identified
    • Generality of feedback loop across tissues untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many parallel kinase inputs, deubiquitylases, and non-CDK substrates are integrated to set CDC25A activity in a given cellular and metabolic context remains unresolved.
  • No unified quantitative model integrating the kinase/DUB network
  • Substrate-selection switch between cell-cycle CDKs and EGFR/ERK/PKM2/TBK1 unknown
  • Structural basis of phosphodegron recognition not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 3 GO:0016787 hydrolase activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-73894 DNA Repair 4 R-HSA-1430728 Metabolism 1 R-HSA-168256 Immune System 1 R-HSA-8953854 Metabolism of RNA 1
Partners
BTRCCDK1CDK2CHEK1NEK11PKM2TBK1USP7
Complex memberships
14-3-3γ/Chk1/CDC25A ternary complexSCF-β-TrCP (substrate)cyclin B-CDK1cyclin E/A-CDK2

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 IR-induced destruction of CDC25A requires both ATM and Chk2-mediated phosphorylation of CDC25A on serine 123. Loss of CDC25A prevents dephosphorylation of CDK2 and blocks DNA replication, placing the ATM-Chk2-CDC25A-CDK2 pathway as the S-phase checkpoint governing radioresistant DNA synthesis. IR treatment of cells with ATM/Chk2 mutants; Chk2 phosphorylation of CDC25A-S123 in vitro; dominant-negative Chk2 alleles unable to bind/phosphorylate CDC25A; CDK2-AF rescue experiments Nature High 11298456
2000 CDC25A is rapidly degraded via the ubiquitin-proteasome pathway in response to UV or ionizing radiation, in a Chk1-dependent but p53-independent manner, resulting in persistent inhibitory tyrosine phosphorylation of CDK2 and S-phase block. Proteasome inhibitor treatment; immunoblotting for CDC25A degradation; Chk1 inhibition with caffeine; overexpression bypassing checkpoint; cell survival assays Science High 10827953
2003 Beta-TrCP (SCF E3 ubiquitin ligase F-box protein) is the direct E3 ligase that targets phosphorylated CDC25A for proteasomal degradation during S phase and in response to DNA damage. siRNA knockdown of beta-TrCP1/2 stabilizes CDC25A and causes radioresistant DNA synthesis. siRNA knockdown of beta-TrCP isoforms; co-immunoprecipitation; in vitro ubiquitination assay; radioresistant DNA synthesis assay Nature High 14603323
2003 SCF-beta-TRCP promotes Chk1-dependent CDC25A ubiquitination in vitro, requiring phosphoserine 79 and phosphoserine 82 as a noncanonical phosphodegron for beta-TrCP recognition, with serine 76 as the Chk1 phosphorylation site that primes this cascade. In vitro ubiquitination reconstitution with SCFbeta-TRCP; phosphosite mutagenesis; siRNA depletion of beta-TRCP; Chk1-dependent assays Genes & development High 14681206
2003 Chk1 mediates CDC25A degradation in response to camptothecin and doxorubicin, and CDC25A overexpression abrogates doxorubicin-induced G2 arrest by dephosphorylating and activating CDK1/Cdc2, establishing a role for CDC25A in the G2/M transition. Chk1 siRNA knockdown; CDC25A overexpression; cell cycle analysis; CDK1 phosphorylation assays The Journal of biological chemistry High 12676925
2002 During mitosis, CDC25A is stabilized by phosphorylation on Ser17 and Ser115 by cyclin B-CDK1, which uncouples it from ubiquitin-proteasome degradation. CDC25A binds and activates cyclin B-CDK1, and its RNAi-mediated downregulation delays mitotic entry. Mass spectrometry phosphosite identification; cyclin B-CDK1 kinase assay; RNAi knockdown; cell cycle synchronization; overexpression studies The EMBO journal High 12411508
2003 Chk1 phosphorylates CDC25A on serine 178 and threonine 507, facilitating 14-3-3 binding. Mutation T507A enhanced CDC25A biological activity, increased binding to cyclin B1, activated cyclin B1-CDK1, and promoted premature mitotic entry, indicating a Chk1/CDC25A/14-3-3 pathway preventing premature mitosis. In vitro Chk1 kinase assay; site-directed mutagenesis; co-immunoprecipitation with 14-3-3; CDK1 activation assays; cell cycle analysis Molecular and cellular biology High 14559997
2002 CDC25A's catalytic mechanism proceeds through a dissociative transition state without a general acid for low leaving group pKa substrates. For high leaving group pKa substrates, glutamic acid 431 is essential for efficient hydrolysis; E431Q mutation abolishes this activity. Kinetic isotope effects; Brønsted analysis; pH dependence studies with aryl phosphates; site-directed mutagenesis of E431 The Journal of biological chemistry High 11805096
2009 NEK11 kinase is required for DNA damage-induced CDC25A degradation and G2/M arrest. CHK1 directly activates NEK11 by phosphorylating it on Ser273, and NEK11 in turn directly phosphorylates CDC25A on residues required for beta-TrCP-mediated polyubiquitylation and degradation. shRNA library screen; NEK11 depletion; direct in vitro phosphorylation of CDC25A by NEK11; CHK1 phosphorylation of NEK11; beta-TrCP ubiquitylation assays; G2/M arrest phenotype Nature cell biology High 19734889
2008 GSK-3beta phosphorylates CDC25A to promote its proteasomal degradation during early cell cycle phases. This phosphorylation requires priming of CDC25A by polo-like kinase 3 (Plk3). In vitro GSK-3beta kinase assay; phosphosite mapping; Plk3 priming assay; proteasome inhibitor rescue; correlation in human tumor tissues Cancer cell High 18167338
2010 Casein kinase 1 alpha (CK1alpha) phosphorylates CDC25A on S79 and S82 in a hierarchical manner requiring prior phosphorylation of S76 by Chk1 or GSK-3beta. This CK1alpha phosphorylation facilitates beta-TrCP binding and ubiquitin-mediated proteolysis throughout interphase and after genotoxic stress. In vitro kinase assays; phosphosite mutagenesis; hierarchical phosphorylation reconstitution; beta-TrCP binding assays Oncogene High 20348946
2010 Dub3 ubiquitin hydrolase binds CDC25A and removes polyubiquitin modifications that mark it for proteasomal degradation. Dub3 knockdown increases CDC25A ubiquitylation and degradation, reducing CDK/cyclin activity and causing G1/S and G2/M arrest. Co-immunoprecipitation; ubiquitylation assays; Dub3 siRNA knockdown; cell cycle analysis; NIH-3T3 transformation; xenograft tumor model Nature cell biology High 20228808
2010 14-3-3gamma forms a complex with Chk1 phosphorylated at Ser296 (autophosphorylation site), and this ternary complex (14-3-3gamma/Chk1/CDC25A) mediates CDC25A phosphorylation and degradation to block premature mitotic entry after DNA damage. Co-immunoprecipitation; phospho-specific antibodies; Chk1-S296A mutant replacement; UV irradiation checkpoint assay; ternary complex characterization The EMBO journal High 20639859
2004 During unperturbed S phase, physiological regulation of the Chk1-CDC25A pathway depends on ATR, Claspin, Rad9, and Hus1. Ablation of ATR inhibits Chk1-dependent phosphorylation of CDC25A and causes CDC25A accumulation without external DNA damage. Chemical and genetic ATR ablation; siRNA depletion of Claspin, Rad9, Hus1; immunoblotting for CDC25A levels and Chk1-S345 phosphorylation Cell cycle Medium 15190204
2002 CDC25A possesses a cyclin-binding (Cy) motif near its N-terminus that is required for association with cyclin E/A-CDK2. Mutations in this motif disrupt CDC25A-cyclin-CDK2 association and selectively block dephosphorylation of cyclin E-CDK2. p21 competitively disrupts this interaction, and CDC25A protects CDK complexes from p21 inhibition. In vitro binding assays with mutant CDC25A constructs; co-immunoprecipitation in vivo; p21 competition assays; Xenopus egg extract reconstitution Molecular and cellular biology High 9234691
2002 CDC25A interacts physically and functionally with EGFR in hepatoma cells. CDC25A dephosphorylates tyrosine-phosphorylated EGFR; purified GST-CDC25A and endogenous CDC25A both dephosphorylate EGFR. The interaction requires the EGFR C-terminus and a functional kinase domain. Co-immunoprecipitation; in vitro phosphatase assay with GST-CDC25A on EGFR; CDC25A inhibitor Cpd5; EGFR mutant constructs The Journal of biological chemistry Medium 11912208
2001 CDC25A physically associates with apoptosis signal-regulating kinase 1 (ASK1) in mammalian cells, co-localizing in the cytoplasm. The C-terminus of CDC25A binds ASK1 adjacent to its kinase domain and inhibits ASK1 kinase activity by reducing ASK1 homo-oligomerization, independent of CDC25A phosphatase activity. Yeast two-hybrid screen; co-immunoprecipitation; confocal immunocytochemistry; inducible transgene expression; ASK1 kinase activity assay; homo-oligomerization assay Molecular and cellular biology High 11416155
2005 CDC25A physically interacts with and dephosphorylates phospho-ERK both in vitro and in cell culture. Inhibition of CDC25A activity with Cpd5 or siRNA knockdown causes ERK hyper-phosphorylation independent of the EGFR pathway. Co-immunoprecipitation; in vitro phosphatase assay on phospho-ERK; siRNA knockdown; CDC25A inactive mutant overexpression; EGFR-devoid cell lines Journal of cellular physiology Medium 15672448
2016 EGFR activation causes c-Src-mediated phosphorylation of CDC25A at Y59, enabling its interaction with nuclear PKM2. CDC25A then dephosphorylates PKM2 at S37, promoting PKM2-dependent beta-catenin transactivation, c-Myc-upregulated glycolytic gene expression (GLUT1, PKM2, LDHA, CDC25A), creating a positive feedback loop that promotes the Warburg effect. Co-immunoprecipitation; in vitro dephosphorylation assay of PKM2 by CDC25A; phosphosite mutagenesis; reporter assays; knockdown/overexpression studies; xenograft tumor model Nature communications High 27485204
2021 CDC25A dephosphorylates nuclear PKM2, suppressing autophagy-dependent ferroptosis in cervical cancer cells by upregulating ErbB2 levels through the PKM2-pH3T11-H3K9Ac pathway. Co-IP; nuclear/cytosolic fractionation; ChIP; dual luciferase assay; siRNA knockdown; xenograft model; cellular ferroptosis assays Cell death & disease Medium 34743185
2018 CDC25A negatively regulates RIG-I-mediated antiviral signaling by interacting with TBK1 and directly dephosphorylating TBK1 at S172, thereby reducing IRF3 phosphorylation and IFN-beta transcription. This inhibitory effect is dependent on CDC25A phosphatase activity. Co-immunoprecipitation; in vitro dephosphorylation assay of TBK1-S172 by CDC25A; siRNA knockdown; luciferase reporter assay; VSV/SeV infection assays Journal of virology High 30021902
2009 In Xenopus eggs, strong ERK activation causes p90RSK-mediated phosphorylation of CDC25A on multiple sites overlapping Chk1 sites, and ERK itself phosphorylates CDC25A, together targeting it for SCF-beta-TrCP-dependent degradation and cell cycle arrest. In vitro phosphorylation of CDC25A by p90RSK and ERK; SCF-beta-TrCP degradation assay; Xenopus egg system; phosphosite mapping Molecular biology of the cell Medium 19244340
2002 In Xenopus embryos, Chk1 (but not Cds1/Chk2) is activated at the midblastula transition and is essential for CDC25A degradation and cell cycle elongation. Chk1-induced CDC25A degradation also requires a prior Chk1-independent phosphorylation at Ser73. Xenopus embryo system; constitutively active Chk1; in vitro phosphorylation; Chk1 inhibition; cell viability assay The EMBO journal Medium 12110582
1999 Serum-induced expression of CDC25A is mediated by an E2F site at -62 in the promoter. In serum-starved cells, p130 and p107 (Rb family members) bind E2F at this site to repress transcription; serum induction correlates with inactivation of p107/p130. Promoter-reporter assays; E2F site mutation; EMSA showing E2F-p107/p130 complex binding; serum induction experiments Molecular and cellular biology Medium 10373518
2006 p53 downregulates CDC25A transcription in a promoter-dependent manner, without directly binding the CDC25A promoter DNA. This requires a functional p53 but is independent of p53-binding sites; mutant p53, p63, and p73 cannot repress CDC25A transcription. p53-inducible cell system; qRT-PCR and immunoblotting; promoter-reporter assays; ChIP (negative result for direct binding); p53/p63/p73 comparison Oncogene Medium 17001315
2008 Dual regulation of CDC25A in DNA damage response occurs at both the protein and transcriptional level: Chk1 promotes rapid protein degradation, while p53-activated ATF3 directly binds the CDC25A promoter to repress transcription. In cells deficient in both Chk1 and p53, CDC25A down-regulation is completely abolished. siRNA screen for checkpoint kinases; ATF3 ChIP on CDC25A promoter; dual KD of Chk1 and p53; cell cycle and cell death assays The Journal of biological chemistry Medium 19060337
2005 In cytokine-dependent lymphocytes, cytokine withdrawal activates p38 MAPK, which phosphorylates CDC25A at S75 and S123, inducing its degradation and leaving CDK/cyclin complexes inactive. Expression of CDC25A mutant (S75A/S123A) renders cells resistant to cytokine withdrawal-induced cycle arrest. p38 MAPK inhibition; phosphosite mutagenesis (S75A, S123A) of CDC25A; cytokine withdrawal assay; CDK activity assay The Journal of cell biology Medium 15928203
2008 In DNA damage-dependent CDC25A degradation, Chk1 (not Chk2) is the primary kinase phosphorylating Ser-76 required for SCF-beta-TrCP-mediated ubiquitination. Chk2 cannot efficiently phosphorylate Ser-76 and cannot support SCFbeta-TRCP-mediated ubiquitination of CDC25A in vitro. In CHK2-/- cells, CDC25A degradation kinetics are normal, but Chk1 depletion in CHK2-/- cells stabilizes CDC25A. In vitro kinase assay comparing Chk1 vs Chk2 on Ser-76; in vitro ubiquitination assay; CHK2-/- HCT116 cells; siRNA depletion of Chk1 in CHK2-/- background The Journal of biological chemistry High 18480045
2017 CyclinD-CDK4/CDK6 complexes directly phosphorylate CDC25A on Ser40 during G1. CyclinD1-CDK4 decreases CDC25A stability in a beta-TrCP-dependent manner, with Ser40 and Ser88 phosphorylations contributing. This creates a negative feedback loop controlling the G1/S transition. In vitro kinase assay of CyclinD-CDK4/6 on CDC25A; phosphosite mutagenesis (Ser40); beta-TrCP dependency; cell cycle synchronization; immunoprecipitation Oncogene Medium 28192398
2021 DYRK2 kinase phosphorylates CDC25A on at least 7 residues, promoting its ubiquitin/proteasome-mediated degradation independently of known CDC25A E3 ubiquitin ligases. CDC25A in turn controls DYRK2 phosphorylation at residues outside its activation loop, affecting DYRK2 localization and activity, forming a mutual feedback regulatory loop. In vitro DYRK2 kinase assay; phosphosite identification; ubiquitin-proteasome degradation assays; DYRK2 localization studies; cell cycle and apoptosis assays Cell death and differentiation Medium 34363019
2015 STK38 (serine-threonine kinase 38) directly phosphorylates CDC25A at Ser-76, and STK38 depletion prevents DNA-damage-induced CDC25A degradation and subsequent G2 arrest. In vitro kinase assay of STK38 on CDC25A; STK38 siRNA depletion; CDC25A stability assay after DNA damage; G2 arrest measurement Cellular signalling Medium 25936524
2018 BRE/BRCC45 facilitates deubiquitylation of CDC25A by recruiting USP7, stabilizing CDC25A in the presence of DNA damage and contributing to cell survival of BRCA2-deficient cells. Insertional mutagenesis screen; co-immunoprecipitation of BRE-USP7-CDC25A; ubiquitylation assays; cell viability assays Nature communications Medium 29416040
2005 CDC25A shuttles dynamically between nucleus and cytoplasm. Nuclear export is partly mediated by an N-terminal nuclear export sequence (NES) not sensitive to leptomycin B (Exportin 1-independent). A nuclear localization signal (NLS) mutation causes cytoplasmic localization. FLIP (fluorescence loss in photobleaching); cell fusion assays; NES/NLS mutagenesis; leptomycin B treatment; live-cell imaging with YFP-CDC25A Experimental cell research Medium 15572030
2013 miR-483-3p directly targets the 3'-UTR of CDC25A mRNA, reducing CDC25A levels and increasing inhibitory tyrosine phosphorylation of CDK4/6, which abolishes CDK4/6 association with D-type cyclins and arrests cells in early G1. Luciferase reporter with CDC25A 3'-UTR; anti-miRNA rescue; CDK4/6 phosphorylation status; cyclin-CDK co-immunoprecipitation; cell cycle synchronization Cell death and differentiation Medium 23429262
2019 Chk1-mediated CDC25A degradation is the primary mechanism by which Chk1 controls normal (unperturbed) cell cycle progression; simultaneous depletion of both Chk1 and CDC25A partially suppresses cell cycle defects caused by Chk1 depletion alone. CRISPR/Cas9 auxin-inducible degron for endogenous Chk1 depletion; simultaneous Chk1+CDC25A depletion epistasis; DNA damage marker accumulation Journal of cell science High 30635443
2011 CDC25A enhances Foxo1 stability by dephosphorylating CDK2, and Foxo1 directly regulates MMP1 transcription. CDC25A overexpression in breast cancer cells enhances metastasis, while downmodulation inhibits it in mouse models, independent of proliferation and apoptosis. CDC25A overexpression/knockdown; Foxo1 stability assays; CDK2 dephosphorylation; MMP1 reporter; mouse metastasis models Molecular and cellular biology Medium 21670150
2008 CDC25A controls meiosis I progression in mouse oocytes: it localizes exclusively to the nucleus prior to NEBD, is degraded at metaphase I by a maturation-associated mechanism, and overexpression blocks meiotic maturation at MI with spindle/chromosome defects. RNAi reduction decreases meiosis resumption and MII transition. GFP-CDC25A microinjection; RNAi; cAMP arrest release; CDK1/MAPK activity assays; immunofluorescence for nuclear localization Developmental biology Medium 18367163
1997 TGF-beta represses CDC25A expression to cause inhibitory tyrosine phosphorylation and inactivation of CDK4 and CDK6 in a human mammary epithelial cell line, independent of its induction of p15INK4B. CDC25A mRNA/protein expression analysis after TGF-beta treatment; CDK4/6 tyrosine phosphorylation assays; epistasis between p15 induction and CDC25A repression Nature Medium 9163429
2017 NPAS2 (a circadian transcription factor) heterodimerizes with BMAL1 and binds E-box elements in the CDC25A promoter to transcriptionally upregulate CDC25A, leading to CDK2/4/6 and Bcl-2 dephosphorylation and promoting hepatocellular carcinoma cell survival. ChIP assay; CDC25A promoter-reporter assay; NPAS2/BMAL1 co-immunoprecipitation; siRNA knockdown; xenograft model Cell death & disease Medium 28333141
2012 FOXM1 directly regulates CDC25A gene transcription via promoter binding and indirect E2F-dependent pathways. CDC25A phosphatase activity enhances FOXM1 transcriptional activity synergistically through CDK1-mediated phosphorylation of FOXM1 at T600, T611, T620. A novel protein interaction between FOXM1 C-terminus and CDC25A is demonstrated. CDC25A promoter-reporter assay; FOXM1 ChIP; co-immunoprecipitation of FOXM1-CDC25A; phosphorylation mutagenesis (T600A, T611A); FOXM1 transcriptional activity assays PloS one Medium 23240008
2021 CDK2/cyclin A mediates feedback inhibition of CDC25A by phosphorylating S88 in a CDK consensus sequence, preventing CDC25A over-activation in early S phase. CDK complexes with cyclin B (and possibly cyclin E) stabilize CDC25A in a feed-forward loop. CDK2 inhibition; cyclin A suppression; S88 phosphorylation analysis; CDC25A stability assays; CHK1 inhibitor experiments Cell cycle Medium 34156324
2022 SRSF10 promotes exon 6 skipping in CDC25A pre-mRNA, producing a truncated isoform CDC25A(ΔE6) that lacks two ubiquitination sites (Lys150, Lys169) in exon 6, rendering it more stable and nucleus-retained. Additionally, SRSF10 activates CDC25A through Ser178 dephosphorylation causing nuclear retention. RNA immunoprecipitation and CLIP-qPCR; RNA sequencing for AS events; co-immunoprecipitation; immunofluorescence; western blotting; in vitro and in vivo HCC models Journal of experimental & clinical cancer research Medium 36539837
2013 SMG-1 kinase phosphorylates CDC25A as a substrate; cells depleted of SMG-1 show prolonged CDC25A stability and fail to inactivate CDK2 in response to radiation, linking SMG-1 to G1/S checkpoint via CDC25A. SMG-1 depletion; CDC25A stability assays after irradiation; CDK2 inactivation assay; tumor growth experiments Cell cycle Low 24107632
2012 Rock2 directly binds CDC25A (co-IP, immunofluorescence colocalization) and regulates CDC25A ubiquitination and degradation. Rock2 knockdown promotes CDC25A ubiquitination and its degradation, causing G1/S arrest. Co-immunoprecipitation; immunofluorescence; Rock2 siRNA; ubiquitination assay; cell cycle analysis Experimental cell research Low 22705122
2011 JAK2(V617F) upregulates CDC25A at the translational level through STAT5 and the translational initiation factor eIF2alpha, without increasing CDC25A transcription or protein stability or upstream Akt/MAPK involvement. Jak2(V617F) knock-in mouse model; JAK2(V617F) cell lines; quantitative PCR for transcription; protein stability assays; STAT5 inhibition; eIF2alpha pathway analysis Blood Medium 22065597

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 857 11298456
2000 Rapid destruction of human Cdc25A in response to DNA damage. Science (New York, N.Y.) 644 10827953
2003 Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Nature 381 14603323
1997 Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature 342 9163429
2003 Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. The Journal of biological chemistry 307 12676925
2003 SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes & development 295 14681206
2009 microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer research 267 19826040
2002 Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability. The EMBO journal 250 12411508
2000 Role of the Cdc25A phosphatase in human breast cancer. The Journal of clinical investigation 182 10995786
2003 Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding. Molecular and cellular biology 177 14559997
2012 The role of Cdc25A in the regulation of cell proliferation and apoptosis. Anti-cancer agents in medicinal chemistry 171 22263797
2004 Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 164 15021892
1997 Overexpression of CDC25A and CDC25B in head and neck cancers. Cancer research 163 9192810
2001 Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Molecular and cellular biology 158 11154267
2016 PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. Nature communications 157 27485204
1998 Overexpression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc. Cancer research 157 9751615
2008 GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. Cancer cell 140 18167338
2008 MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. The Journal of clinical investigation 139 18949056
2002 Chk1 is activated transiently and targets Cdc25A for degradation at the Xenopus midblastula transition. The EMBO journal 118 12110582
2019 Exosome-derived miR-339-5p mediates radiosensitivity by targeting Cdc25A in locally advanced esophageal squamous cell carcinoma. Oncogene 110 30858545
2010 Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A. Nature cell biology 110 20228808
2017 Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway. Molecular cancer 103 28651608
2009 NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint. Nature cell biology 102 19734889
2012 PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. Cell cycle (Georgetown, Tex.) 101 23032366
2004 ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damage. Cell cycle (Georgetown, Tex.) 101 15190204
1997 p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases. Molecular and cellular biology 98 9234691
2000 Cell cycle-related phosphatases CDC25A and B expression correlates with survival in ovarian cancer patients. Anticancer research 91 11205229
2001 The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1. Molecular and cellular biology 84 11416155
2021 Cdc25A inhibits autophagy-mediated ferroptosis by upregulating ErbB2 through PKM2 dephosphorylation in cervical cancer cells. Cell death & disease 83 34743185
1999 Serum-induced expression of the cdc25A gene by relief of E2F-mediated repression. Molecular and cellular biology 77 10373518
2010 14-3-3gamma mediates Cdc25A proteolysis to block premature mitotic entry after DNA damage. The EMBO journal 74 20639859
2007 Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice. Cancer research 73 17638870
2008 CDC25A phosphatase: a rate-limiting oncogene that determines genomic stability. Cancer research 68 18316586
2020 Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors. Oncogenesis 67 33028815
2000 Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation. Oncogene 66 10828887
2014 Downregulation of LncRNAH19 and MiR-675 promotes migration and invasion of human hepatocellular carcinoma cells through AKT/GSK-3β/Cdc25A signaling pathway. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 65 24939300
2007 Bendamustine induces G2 cell cycle arrest and apoptosis in myeloma cells: the role of ATM-Chk2-Cdc25A and ATM-p53-p21-pathways. Journal of cancer research and clinical oncology 63 17653574
2007 Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability. Cancer research 60 17283130
2000 cdc25a and the splicing variant cdc25b2, but not cdc25B1, -B3 or -C, are over-expressed in aggressive human non-Hodgkin's lymphomas. International journal of cancer 60 10754492
2008 CDC25A phosphatase controls meiosis I progression in mouse oocytes. Developmental biology 59 18367163
2001 Clinical significance of CDC25A and CDC25B expression in squamous cell carcinomas of the oesophagus. British journal of cancer 59 11487274
2017 NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A. Cell death & disease 57 28333141
2011 Cdc25A regulates matrix metalloprotease 1 through Foxo1 and mediates metastasis of breast cancer cells. Molecular and cellular biology 56 21670150
2005 Cytokine-driven cell cycling is mediated through Cdc25A. The Journal of cell biology 56 15928203
2015 MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma. PloS one 53 25909324
2010 Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction. Oncogene 53 20348946
2017 Stat3/Cdc25a-dependent cell proliferation promotes embryonic axis extension during zebrafish gastrulation. PLoS genetics 52 28222105
2006 p53 downregulates expression of the G1/S cell cycle phosphatase Cdc25A. Oncogene 52 17001315
2013 CDC25A targeting by miR-483-3p decreases CCND-CDK4/6 assembly and contributes to cell cycle arrest. Cell death and differentiation 51 23429262
2007 Hypoxic suppression of the cell cycle gene CDC25A in tumor cells. Cell cycle (Georgetown, Tex.) 50 17671423
2006 The Chk1/Cdc25A pathway as activators of the cell cycle in neuronal death induced by camptothecin. The Journal of neuroscience : the official journal of the Society for Neuroscience 50 16928871
2002 Identification of epidermal growth factor receptor as a target of Cdc25A protein phosphatase. The Journal of biological chemistry 50 11912208
1998 Elevated expression of the cdc25A protein phosphatase in colon cancer. Experimental cell research 49 9596996
2018 MicroRNA-99a-5p suppresses breast cancer progression and cell-cycle pathway through downregulating CDC25A. Journal of cellular physiology 46 30443946
2008 Differential roles for checkpoint kinases in DNA damage-dependent degradation of the Cdc25A protein phosphatase. The Journal of biological chemistry 45 18480045
2002 The catalytic mechanism of Cdc25A phosphatase. The Journal of biological chemistry 45 11805096
2000 Reduction of Cdc25A contributes to cyclin E1-Cdk2 inhibition at senescence in human mammary epithelial cells. Oncogene 45 11103932
2015 Anti-Colon Cancer Effects of 6-Shogaol Through G2/M Cell Cycle Arrest by p53/p21-cdc2/cdc25A Crosstalk. The American journal of Chinese medicine 44 26119958
2015 MicroRNA-184 Deregulated by the MicroRNA-21 Promotes Tumor Malignancy and Poor Outcomes in Non-small Cell Lung Cancer via Targeting CDC25A and c-Myc. Annals of surgical oncology 43 25990966
2020 Circular RNA circ_0007142 Facilitates Colorectal Cancer Progression by Modulating CDC25A Expression via miR-122-5p. OncoTargets and therapy 40 32431519
2006 Cell adhesion regulates CDC25A expression and proliferation in acute myeloid leukemia. Cancer research 40 16854822
2019 Chk1-mediated Cdc25A degradation as a critical mechanism for normal cell cycle progression. Journal of cell science 37 30635443
2017 CyclinD-CDK4/6 complexes phosphorylate CDC25A and regulate its stability. Oncogene 37 28192398
2012 Novel interactions between FOXM1 and CDC25A regulate the cell cycle. PloS one 36 23240008
2009 Hypoxia-mediated regulation of Cdc25A phosphatase by p21 and miR-21. Cell cycle (Georgetown, Tex.) 36 19738433
2008 Dual regulation of Cdc25A by Chk1 and p53-ATF3 in DNA replication checkpoint control. The Journal of biological chemistry 35 19060337
2018 BRE/BRCC45 regulates CDC25A stability by recruiting USP7 in response to DNA damage. Nature communications 34 29416040
2012 Rock2 regulates Cdc25A through ubiquitin proteasome system in hepatocellular carcinoma cells. Experimental cell research 34 22705122
2005 Cdc25A localisation and shuttling: characterisation of sequences mediating nuclear export and import. Experimental cell research 34 15572030
2005 Cdc25A and ERK interaction: EGFR-independent ERK activation by a protein phosphatase Cdc25A inhibitor, compound 5. Journal of cellular physiology 34 15672448
2016 YBX1 regulates tumor growth via CDC25a pathway in human lung adenocarcinoma. Oncotarget 33 27384875
2009 The extracellular signal-regulated kinase-mitogen-activated protein kinase pathway phosphorylates and targets Cdc25A for SCF beta-TrCP-dependent degradation for cell cycle arrest. Molecular biology of the cell 32 19244340
2008 Aberrant Polo-like kinase 1-Cdc25A pathway in metastatic hepatocellular carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 32 18980975
2021 A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival. Cell death and differentiation 31 34363019
2020 B7-H3 promotes the cell cycle-mediated chemoresistance of colorectal cancer cells by regulating CDC25A. Journal of Cancer 30 32127943
2013 SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways. Cell cycle (Georgetown, Tex.) 30 24107632
2005 Differential impact of diverse anticancer chemotherapeutics on the Cdc25A-degradation checkpoint pathway. Experimental cell research 30 15561098
2001 Cdc25A phosphatase suppresses apoptosis induced by serum deprivation. Oncogene 30 11494150
2018 SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A. Oncology letters 29 29552180
2010 CDC25A mRNA levels significantly correlate with Ki-67 expression in human glioma samples. Journal of neuro-oncology 29 20217459
2004 Expression of cdc25A and cdc25B phosphatase in breast carcinoma. Breast cancer (Tokyo, Japan) 29 15550849
2002 Expression of cdc25A and cdc25B proteins in thyroid neoplasms. British journal of cancer 29 12085185
2018 CDC25A pathway toward tumorigenesis: Molecular targets of CDC25A in cell-cycle regulation. Journal of cellular biochemistry 28 30443958
2018 Phosphatase Cdc25A Negatively Regulates the Antiviral Immune Response by Inhibiting TBK1 Activity. Journal of virology 27 30021902
2011 CDC25A, VAV1, TP73, BRCA1 and ZAP70 gene overexpression correlates with radiation response in colorectal cancer. Oncology reports 27 21344162
2007 CDC25A levels determine the balance of proliferation and checkpoint response. Cell cycle (Georgetown, Tex.) 27 18073536
2017 Accumulation of cytoplasmic CDC25A in cutaneous squamous cell carcinoma leads to a dependency on CDC25A for cancer cell survival and tumor growth. Cancer letters 26 28951130
2010 NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling. Cell cycle (Georgetown, Tex.) 26 20090422
2022 SRSF10 stabilizes CDC25A by triggering exon 6 skipping to promote hepatocarcinogenesis. Journal of experimental & clinical cancer research : CR 25 36539837
2019 CDC25A Facilitates Chemo-resistance in Ovarian Cancer Multicellular Spheroids by Promoting E-cadherin Expression and Arresting Cell Cycles. Journal of Cancer 25 31281464
2017 Ciclopirox inhibits cancer cell proliferation by suppression of Cdc25A. Genes & cancer 25 28680535
2011 The cell cycle regulator CDC25A is a target for JAK2V617F oncogene. Blood 25 22065597
2010 Inhibition of androgen receptor and Cdc25A phosphatase as a combination targeted therapy in molecular apocrine breast cancer. Cancer letters 25 20605569
2009 CDC25A and B dual-specificity phosphatase inhibitors: potential agents for cancer therapy. Current medicinal chemistry 25 19442149
2021 Activation of CDC25A phosphatase is limited by CDK2/cyclin A-mediated feedback inhibition. Cell cycle (Georgetown, Tex.) 24 34156324
2008 CDC25A: a rebel within the CDC25 phosphatases family? Anti-cancer agents in medicinal chemistry 24 19075564
2006 Association of spermatogenic failure with decreased CDC25A expression in infertile men. Human reproduction (Oxford, England) 24 16720623
2022 Hsa_circ_0014879 regulates the radiosensitivity of esophageal squamous cell carcinoma through miR-519-3p/CDC25A axis. Anti-cancer drugs 23 34407051
2015 Serine-Threonine Kinase 38 regulates CDC25A stability and the DNA damage-induced G2/M checkpoint. Cellular signalling 23 25936524
2011 Widdrol activates DNA damage checkpoint through the signaling Chk2-p53-Cdc25A-p21-MCM4 pathway in HT29 cells. Molecular and cellular biochemistry 23 22160829

Missed literature

Know a paper Affinage missed for CDC25A? Flag it for the maintainers and the community.

No submissions yet.