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Cdc25

Cdc25 phosphatases constitute a family of dual-specificity protein phosphatases essential for eukaryotic cell cycle progression, primarily functioning to activate cyclin-dependent kinases (CDKs) by removing inhibitory phosphate groups from specific residues, such as Thr14 and Tyr15 on CDK1.^[1] These enzymes were first identified in 1986 in the fission yeast Schizosaccharomyces pombe by Paul Nurse and colleagues as the product of the cdc25+ gene, a key positive regulator required for entry into mitosis.^[2] In mammals, three homologous isoforms—Cdc25A, Cdc25B, and Cdc25C—have evolved, each with distinct spatiotemporal expression patterns and regulatory mechanisms to orchestrate transitions through G1/S, S phase, and G2/M checkpoints.^[3] The Cdc25 family shares a conserved catalytic domain but differs in their N-terminal regulatory regions, which confer substrate specificity and responsiveness to upstream signals like DNA damage checkpoints mediated by kinases such as Chk1 and Chk2.^[4] Cdc25A primarily drives G1/S progression and is rapidly degraded after DNA replication to prevent unscheduled cell cycle advancement, while Cdc25B initiates the G2/M transition by activating CDK1-cyclin B complexes at centrosomes.^[1] Cdc25C, in turn, amplifies mitotic entry and is tightly controlled during the DNA damage response to halt progression until repairs are complete.^[5] Dysregulation of these phosphatases, often through overexpression or mutation, disrupts checkpoint integrity and promotes genomic instability. Overexpression of Cdc25 isoforms is frequently observed in various human cancers, including breast, lung, and colorectal tumors, where it correlates with poor prognosis and resistance to chemotherapy by accelerating cell proliferation and evading DNA damage-induced arrest.^[3] Consequently, Cdc25 phosphatases have emerged as promising therapeutic targets, with small-molecule inhibitors under investigation to restore cell cycle control in malignancies like acute myeloid leukemia.^[6] Their role extends beyond cancer to developmental processes and responses to genotoxic stress, underscoring their fundamental importance in cellular homeostasis.

Introduction and Discovery

Historical Background

The cdc25 gene was first identified in the fission yeast Schizosaccharomyces pombe through the isolation of temperature-sensitive mutants that arrest in the G2 phase of the cell cycle, preventing progression to mitosis and resulting in elongated cells at the restrictive temperature. These key experiments, conducted by Fantes in 1979, demonstrated that cdc25 is essential for the G2/M transition, as mutant cells failed to initiate mitosis despite continued growth. In the 1980s, further characterization revealed cdc25's role as a positive regulator of mitosis. The gene was cloned by Russell and Nurse in 1986 using complementation of temperature-sensitive mutants, showing that increased cdc25 expression advances mitotic entry at reduced cell sizes, establishing it as a dosage-dependent inducer. A homolog in budding yeast (Saccharomyces cerevisiae), known as MIH1, was cloned and characterized around the same period, linking it to activation of the cyclin-dependent kinase Cdc28 (the budding yeast ortholog of Cdc2/Cdk1). Milestone work in 1990 by Moreno, Nurse, and Russell highlighted the cyclic accumulation of the Cdc25 protein during the cell cycle, peaking at G2/M to drive mitotic induction. The following year, Millar et al. from Russell's group demonstrated that Cdc25 possesses intrinsic dual-specificity phosphatase activity, directly dephosphorylating inhibitory tyrosine residues on Cdc2 to activate the kinase for mitotic entry. The discovery extended to mammals in the early 1990s, with identification of multiple isoforms reflecting evolutionary conservation of Cdc25 function. Cdc25C, the first mammalian homolog, was cloned in 1990 by Sadhu et al. as a nuclear protein predominantly expressed in G2 and required for mitotic initiation. Cdc25A and Cdc25B were described in 1991 by Galaktionov and Beach as phosphatases with roles in early cell cycle progression, distinct from the G2/M-specific Cdc25C.^[7] These findings solidified Cdc25 as a conserved family of regulators linking cell cycle checkpoints to cyclin-dependent kinase activation.

Definition and Nomenclature

The Cdc25 phosphatases constitute a family of dual-specificity protein phosphatases within the protein tyrosine phosphatase (PTP) superfamily, distinguished by their capacity to dephosphorylate both phosphotyrosine and phosphothreonine residues on substrate proteins. These enzymes play a pivotal role in cell cycle regulation by activating cyclin-dependent kinase (CDK) complexes through the removal of inhibitory phosphate groups. Originally identified in the fission yeast Schizosaccharomyces pombe as the product of the cdc25 gene essential for mitotic entry, the nomenclature reflects species-specific conventions: lowercase "cdc25" denotes the genes and proteins in yeast orthologs. In humans and other mammals, the orthologous genes are designated with uppercase "CDC25," comprising three primary isoforms—CDC25A, CDC25B, and CDC25C—each encoded by distinct loci on separate chromosomes: CDC25A at 3p21.1, CDC25B at 20p13.1, and CDC25C at 5q31.2.^[8]^[9] Orthologs in non-mammalian species exhibit varied nomenclature; for instance, in Drosophila melanogaster, the two Cdc25 homologs are known as String, which regulates mitotic divisions, and Twine, which controls meiotic progression. This conserved family underscores Cdc25's fundamental function in promoting cell cycle advancement across eukaryotes via CDK activation.

Structural Features

Domain Organization

The Cdc25 family of dual-specificity phosphatases exhibits a conserved modular architecture comprising an N-terminal regulatory domain and a C-terminal catalytic domain, which together enable their roles in cell cycle control. The N-terminal regulatory domain varies in length across isoforms, typically spanning 200 to 400 residues, and serves as a platform for interactions with binding partners while harboring potential phosphorylation sites that influence protein stability and localization. This region displays low sequence conservation among isoforms (20-25% identity) and is characterized as intrinsically disordered in Cdc25A, Cdc25B, and Cdc25C, contributing to its flexibility in regulatory functions.^[6]^[10]^[11]^[12] In contrast, the C-terminal catalytic domain is highly conserved (approximately 60% pairwise identity between isoforms) and consists of 150 to 200 residues that fold into a compact protein tyrosine phosphatase (PTP)-like structure. This domain features key signature motifs, including the HCX₅R loop that coordinates the catalytic cysteine residue essential for phosphotyrosine dephosphorylation. Early structural studies, including X-ray crystallography of the Cdc25A catalytic domain at 2.3 Å resolution in 1998 and subsequent analyses of Cdc25B around 2000, revealed an α/β fold with a central five-stranded β-sheet surrounded by α-helices, distinct from classical PTPs yet functionally analogous. NMR spectroscopy further confirmed the compact, stable nature of this domain in isolation.^[6]^[13]^[14] Isoform-specific variations in domain organization underscore their distinct temporal roles in the cell cycle. Cdc25A possesses a relatively shorter N-terminal domain (approximately 313 residues) compared to Cdc25B (about 384 residues), potentially influencing its rapid turnover and broad activity. Cdc25C, with an N-terminal region of around 260 residues, includes nuclear localization signals (NLS) such as a bipartite basic motif involving residues 298-315, facilitating its nuclear accumulation during G2/M progression. Overall, the full-length proteins range in size from approximately 53 kDa (Cdc25C, 473 residues) to 65 kDa (Cdc25B, 580 residues), with Cdc25A at about 59 kDa (524 residues), reflecting these domain length differences.^[15]^[16]^[17]^[18]

Catalytic Site

The catalytic site of Cdc25 phosphatases is characterized by a conserved active site geometry that deviates from classical protein tyrosine phosphatases (PTPs), featuring a shallow pocket adapted for dual-specificity dephosphorylation of phosphothreonine and phosphotyrosine residues. Central to this site is the signature motif HCX₅R, where the cysteine residue (e.g., Cys430 in Cdc25A, Cys473 in Cdc25B) serves as the nucleophile, and the arginine (e.g., Arg436 in Cdc25A, Arg479 in Cdc25B) stabilizes the negatively charged phosphate group through electrostatic interactions during catalysis. Unlike classical PTPs, which rely on a histidine or aspartate in a WPD loop as the general acid, Cdc25 employs a conserved aspartate (e.g., Asp383 in Cdc25A) positioned to act as the general acid, protonating the leaving group in the first catalytic step and facilitating the second step as a general base.^[19] The reaction proceeds via a two-step mechanism typical of cysteine-based phosphatases. In the first step, the deprotonated thiolate of the catalytic cysteine performs a nucleophilic attack on the substrate's phosphate group, displacing the protein leaving group and forming a transient phosphoenzyme intermediate covalently bound to the cysteine. This is followed by a second step where a water molecule, activated by the conserved aspartate, hydrolyzes the phosphocysteine intermediate, releasing inorganic phosphate and regenerating the enzyme. This aspartate-based catalysis ensures efficient turnover without the structural constraints of a mobile WPD loop, contributing to the enzyme's specificity for protein substrates over small-molecule analogs.^[20] Cdc25 phosphatases exhibit high specificity for the inhibitory phosphorylation sites Thr14 and Tyr15 on cyclin-dependent kinases (CDKs), enabling targeted activation during cell cycle progression. The shallow active site geometry facilitates direct access to these residues within the CDK activation segment. A 2024 cryo-EM structure of the CDK2-cyclin A-CDC25A complex at 2.7 Å resolution revealed a previously unrecognized C-terminal helix of CDC25A (residues 495-524) binding at the CDK2-cyclin A interface, stabilizing the complex and providing insights into substrate recognition.^[20]^[21] In vitro kinetic assays indicate moderate affinity and turnover rates for substrates, with catalytic rate constants (kₐₜ) around 1–2 s⁻¹ based on phosphoenzyme breakdown, underscoring efficient processing of physiological targets despite the enzyme's broad dual-specificity potential. These parameters were derived from studies using purified catalytic domains and peptide mimics of CDK sites, highlighting the site's evolutionary optimization for cell cycle regulation.^[22] Structural insights into the catalytic site were provided by the crystal structure of the Cdc25B catalytic domain at 2.2 Å resolution, revealing a compact α/β fold with a shallow, open active site pocket that lacks deep substrate-binding grooves typical of classical PTPs. This structure, determined in an inhibitor-bound state, illustrates how the catalytic cysteine and adjacent residues form a flexible loop that accommodates bulky CDK substrates, while also exposing vulnerabilities for oxidative inactivation via disulfide bond formation.^[23]

Biochemical Function

Dephosphorylation of CDKs

Cdc25 phosphatases activate cyclin-dependent kinases (CDKs) by removing inhibitory phosphate groups from specific residues in the ATP-binding domain of CDK1 and CDK2. These residues include threonine 14 (Thr14) and tyrosine 15 (Tyr15), which are phosphorylated by kinases such as Wee1 and Myt1 to maintain CDK inactivity during interphase. All three Cdc25 isoforms (A, B, and C) dephosphorylate both Thr14 and Tyr15 on CDK1 and CDK2, with isoform-specific preferences; for example, Cdc25A shows a particular preference for Thr14 on CDK2.^[24] This dephosphorylation relieves steric hindrance in the active site, enabling ATP binding and full kinase activation. The activation primarily targets cyclin-bound CDK complexes critical for cell cycle progression. Cdc25C dephosphorylates the cyclin B-CDK1 complex, promoting entry into mitosis by enhancing CDK1's ability to phosphorylate substrates involved in nuclear envelope breakdown and chromosome condensation. Similarly, Cdc25A acts on cyclin E-CDK2 and cyclin A-CDK2 complexes to facilitate the G1/S transition, where CDK2 drives DNA replication initiation. These actions ensure timely progression through the cell cycle by counterbalancing inhibitory phosphorylations.^[25] Cdc25-mediated activation follows a stepwise model characterized by sequential dephosphorylation, beginning with Tyr15 followed by Thr14, which exhibits positive cooperativity to amplify the response. Initial removal of the Tyr15 phosphate partially activates the CDK, facilitating subsequent Thr14 dephosphorylation and full catalytic competence. This ordered process, observed in biochemical assays, ensures a sharp transition in CDK activity rather than gradual activation. Recent structural studies, including a 2024 cryo-EM structure of the CDK2-cyclin A-CDC25A complex, have elucidated the molecular basis of substrate recognition and dephosphorylation.^[21] In vitro studies from the 1990s demonstrated Cdc25's role using cell-free Xenopus egg extracts, where recombinant Cdc25 reconstituted CDK activity by dephosphorylating inhibited cyclin B-CDK1 complexes, inducing mitotic events such as germinal vesicle breakdown. These assays confirmed that Cdc25 directly reverses inhibitory phosphorylation without requiring additional factors, establishing its essential function in CDK activation. A key regulatory feature is the positive feedback loop where activated CDKs phosphorylate Cdc25 on multiple sites, enhancing its phosphatase activity and subcellular localization. For instance, CDK1 phosphorylates Cdc25C on residues such as Thr48 and Ser214, increasing its catalytic efficiency toward CDK1 itself, thereby amplifying mitotic entry. This multisite phosphorylation creates an ultrasensitive switch for rapid cell cycle advancement.

Substrate Specificity

Cdc25 phosphatases display isoform-specific preferences for their primary substrates, which are the inhibitory phosphorylation sites on cyclin-dependent kinases (CDKs). Cdc25A predominantly dephosphorylates CDK2 at Thr14 and Tyr15, facilitating activation of CDK2-cyclin E and CDK2-cyclin A complexes during the G1/S transition.^[26] In contrast, Cdc25B and Cdc25C primarily target CDK1 at the same sites, activating CDK1-cyclin B for mitotic entry, with Cdc25B initiating this at centrosomes in late G2 phase and Cdc25C contributing in the nucleus during prometaphase.^[3] These preferences arise from structural interactions, as demonstrated by kinetic assays showing Cdc25A's high catalytic efficiency (k_{cat}/K_m \approx 10^6 \, M^{-1} s^{-1}) toward the CDK2-pTpY-cyclin A complex, while Cdc25C exhibits negligible activity against it.^[27] Beyond core CDKs, Cdc25 isoforms show varying breadth in substrate recognition. Cdc25A exhibits the broadest activity, extending to early G1/S CDKs and potentially other phosphoproteins, whereas Cdc25B is more restricted to mitotic contexts and CDK1-specific activation, and Cdc25C is largely nuclear and focused on late G2/M targets.^[28] Experimental phosphoproteomics and mutagenesis studies from the 2000s have elucidated these differences, identifying a preference for substrates with basic residues (e.g., arginine or lysine) adjacent to the phospho-Thr or phospho-Tyr sites, which enhance binding to the Cdc25 catalytic domain.^[29] For instance, substrate-trapping mutants (e.g., D424N in Cdc25A) and docking simulations with CDK2-pTpY-cyclin A confirmed that basic motifs near the phosphorylation site stabilize the enzyme-substrate complex, with the HCX5R catalytic motif playing a key role in hydrolysis.^[28] Evidence for secondary substrates beyond CDKs is limited and context-dependent, often involving low-affinity interactions.

Regulation Mechanisms

Post-Translational Modifications

Cdc25 phosphatases undergo extensive post-translational modifications, primarily phosphorylation, which modulate their activity, stability, and localization. Each isoform possesses multiple phosphorylation sites, with specific examples including at least 13 sites on Cdc25B by Plk1 and 5 on Cdc25C by CDK1, and activating phosphorylations occurring on serine/threonine residues by kinases such as CDK1/2 and Plk1, enhancing catalytic efficiency during cell cycle progression. For instance, CDK1 phosphorylates Cdc25C at multiple sites including Thr48, Thr67, Thr138, Ser205, and Ser285, promoting its activation at the G2/M transition.^[4] Inhibitory phosphorylations, conversely, are mediated by checkpoint kinases like CHK1 and CHK2; a key example is CHK1 phosphorylation of Cdc25C at Ser216, which creates a binding site for 14-3-3 proteins and inhibits phosphatase activity.^[30] Mass spectrometry studies from the 1990s and 2000s, such as those by Peng et al. (1997), mapped these sites and demonstrated that mutants lacking specific phosphorylation sites, like Ser/Thr-to-Ala substitutions on Cdc25B, abolish activation by Plk1 at 13 sites (e.g., Ser50, Thr58).^[31]^[4] Ubiquitination represents another critical modification, particularly for Cdc25A, where SCF^β-TrCP E3 ligase targets the protein for proteasomal degradation following CHK1-mediated phosphorylation at Ser76. This process maintains Cdc25A half-life at approximately 30 minutes during G1 phase, preventing untimely CDK activation.^[32] Busino et al. (2003) showed that this degradation pathway is essential for DNA damage responses, as β-TrCP depletion stabilizes Cdc25A and hyperactivates CDK2.^[32] Additional modifications include acetylation. Acetylation of Cdc25A by ARD1 at lysine residues increases its stability by inhibiting ubiquitination, extending half-life beyond 15 minutes and reducing phosphatase activity in response to genotoxic stress.^[33] Recent studies have also highlighted post-transcriptional regulation, such as N6-methyladenosine (m6A) modification enhancing Cdc25A mRNA stability to promote G1/S transition in cancers like esophageal squamous cell carcinoma (as of 2024).^[34] Temporal dynamics are evident in mitosis, where Cdc25C undergoes hyperphosphorylation at over 15 sites by CDK1, including 11 confirmed Ser/Thr-Pro motifs, sharpening the mitotic entry switch; mutants like Cdc25-13A delay this process and alter cell cycle timing.^[35] In DNA damage scenarios, inhibitory phosphorylations dominate, such as CHK1/CHK2 targeting Cdc25A at Ser123, Ser178, Ser278, and Ser292, accelerating its degradation to enforce G2 arrest.^[30] These modifications, elucidated through 1990s-2000s studies like Hoffmann et al. (1994) on site mapping, ensure precise regulation of Cdc25 function, with recent structural insights from cryo-EM (2024) revealing how N-terminal phosphorylation sites influence Cdc25A interactions with CDK2-cyclin A complexes.^[36]^[21]

Cellular Localization and Binding Partners

Cdc25 phosphatases exhibit dynamic subcellular localization that is critical for their spatiotemporal regulation during the cell cycle, mediated by specific nuclear localization signals (NLS) and nuclear export signals (NES). In Cdc25C, a bipartite NLS located in the regulatory domain facilitates nuclear import, allowing the phosphatase to access nuclear cyclin-dependent kinase (CDK) substrates. Conversely, Cdc25A and Cdc25B contain N-terminal NES motifs that promote cytoplasmic retention via CRM1-dependent export until activation signals trigger nuclear translocation. Mutation of the Cdc25A NES results in predominant nuclear accumulation, underscoring its role in shuttling dynamics.^[37]^[38]^[39] The three mammalian Cdc25 isoforms display distinct localization patterns aligned with their cell cycle roles. Cdc25A shuttles between the nucleus and cytoplasm throughout interphase, enabling regulation of G1/S and S-phase progression. Cdc25B is primarily cytoplasmic during S and G2 phases but translocates to the nucleus at prophase to initiate mitotic entry. In contrast, Cdc25C is predominantly nuclear, though it can be sequestered in the cytoplasm during interphase via interactions that mask its NLS. These patterns were elucidated through fluorescence microscopy studies tracking isoform-specific GFP fusions in synchronized cells.^[40]^[18] Key binding partners modulate Cdc25 localization to ensure precise timing of activity. The 14-3-3 proteins bind phosphorylated Cdc25C at Ser-216, occluding its NLS and sequestering it in the cytoplasm during interphase to prevent premature mitotic activation. Polo-like kinase 1 (Plk1) phosphorylates Cdc25C at Ser-198 within its NES, promoting nuclear import during prophase and facilitating G2/M transition. Co-immunoprecipitation assays from the early 2000s confirmed these interactions and their impact on shuttling. Additionally, Cdc25 forms complexes with cyclin-CDK substrates through N-terminal RXL docking motifs, which bind the hydrophobic patch on cyclins to enhance substrate access and specificity.^[41]^[42]^[43]^[44]

Role in Cell Cycle Progression

G1/S Transition

Cdc25A plays a central role in the G1/S transition by dephosphorylating cyclin-dependent kinase 2 (CDK2) complexes bound to cyclin E or cyclin A, thereby activating these kinases to drive progression into S phase.^[45] This activation enables CDK2-cyclin E/A to phosphorylate the retinoblastoma protein (Rb) on multiple sites, resulting in Rb hyperphosphorylation and the release of bound E2F transcription factors.^[46] Freed E2F then induces the transcription of S-phase genes, including those encoding DNA replication machinery components like DNA polymerase and thymidine kinase, facilitating the initiation of DNA synthesis.^[46] Cdc25A protein levels accumulate and peak during late G1 and early S phase, coinciding with the need for CDK2 activation to commit cells to replication.^[47] Following S-phase entry, Cdc25A undergoes rapid ubiquitin-mediated proteasomal degradation, primarily through SCF^β-TrCP and other E3 ligases, which prevents excessive CDK activity and potential re-replication of the genome.^[48] ^[49] This tightly controlled turnover ensures that Cdc25A function is temporally restricted to the G1/S boundary. In the context of DNA damage checkpoints, CHK2 kinase phosphorylates Cdc25A at specific serine residues (e.g., Ser123), promoting its ubiquitination and degradation, which inhibits CDK2 activation and enforces G1/S arrest to permit DNA repair before replication.^[50] ^[51] This mechanism integrates genotoxic stress signals to halt cell cycle progression, highlighting Cdc25A's role as a key checkpoint effector. Overexpression of Cdc25A in mammalian cell lines, such as human fibroblasts, accelerates the G1/S transition by enhancing CDK2 activity and reducing the duration of G1 phase, leading to premature S-phase entry.^[52] In yeast, the Cdc25 homolog Mih1 dephosphorylates CDK orthologs (e.g., Cdc28 in Saccharomyces cerevisiae) to regulate cell cycle transitions, with analogous functions in promoting phase-specific progression despite differences in primary timing.^[53]

G2/M Transition

Cdc25B initiates the G2/M transition through its localization to centrosomes and subsequent nuclear import during prophase, where it dephosphorylates and activates the CDK1-cyclin B complex, promoting centrosome separation and early mitotic events. This activation occurs specifically at centrosomes, highlighting Cdc25B's unique role in triggering mitotic entry independent of nuclear events initially. In contrast, Cdc25C contributes to the amplification and maintenance of CDK1 activity once mitosis is underway. The hyperphosphorylated form of Cdc25C, generated by multisite phosphorylation during mitotic entry, enhances its phosphatase activity and sustains CDK1-cyclin B activation through metaphase by continuously dephosphorylating inhibitory sites on CDK1. This persistent activity ensures the high CDK1 levels required for proper chromosome congression and metaphase maintenance. The spindle assembly checkpoint (SAC), involving BubR1 as a key component of the mitotic checkpoint complex, inhibits the anaphase-promoting complex/cyclosome (APC/C) until chromosomes achieve bipolar attachment and alignment at the metaphase plate. This checkpoint indirectly supports Cdc25C's role by preventing premature cyclin B degradation, thereby allowing sustained CDK1 activity facilitated by Cdc25C until alignment is complete. BubR1's pseudokinase domain contributes to APC/C inhibition, ensuring mitotic fidelity during this Cdc25C-dependent phase. Experimental evidence underscores these roles: microinjection of neutralizing anti-Cdc25 antibodies into immature starfish oocytes prevents Cdc25 activation, blocking cdc2 kinase (CDK1 homolog) activation and halting mitotic entry, demonstrating Cdc25's essential function in M-phase initiation. In human HeLa cells, Cdc25B overexpression induces premature mitosis from S or G2 phases, often bypassing DNA replication completion, whereas Cdc25C requires G2 phase and co-expression with cyclin B to promote entry, indicating distinct temporal contributions to the G2/M transition. A critical positive feedback loop amplifies this process, as activated CDK1 phosphorylates Cdc25B and Cdc25C at multiple sites (e.g., S323 on Cdc25B and T48, T67 on Cdc25C), enhancing their activities and further activating CDK1, thereby committing cells irreversibly to mitosis. This ultrasensitive loop refines the abrupt switch from G2 to M phase, with distributive phosphorylation ensuring rapid amplification. Post-translational modifications, such as these phosphorylations, tightly regulate the loop's timing.

Evolutionary Aspects

Conservation Across Species

The Cdc25 family of dual-specificity phosphatases demonstrates remarkable evolutionary conservation across eukaryotes, reflecting their fundamental role in cell cycle regulation. The catalytic domain, responsible for dephosphorylating cyclin-dependent kinases (CDKs) at inhibitory threonine and tyrosine residues, exhibits approximately 37% sequence identity between the human Cdc25 proteins and their ortholog in fission yeast (Schizosaccharomyces pombe).^[54] This domain's core motifs, including the active site HCX5R signature, are highly preserved, enabling Cdc25 to activate CDKs universally and ensuring progression through the cell cycle phases. The conservation extends to the functional mechanism, where Cdc25 counteracts inhibitory phosphorylation on conserved Thr14 and Tyr15 sites of CDKs, a feature shared from unicellular yeasts to multicellular metazoans.^[55] Orthologs of Cdc25 vary in number and similarity across species, highlighting both preservation and adaptation within eukaryotes. In S. pombe, a single Cdc25 isoform serves as the primary mitotic inducer, essential for dephosphorylating Cdc2 (the CDK homolog) to trigger mitosis.^[56] The budding yeast Saccharomyces cerevisiae possesses Mih1 as its Cdc25 ortholog, which shares lower sequence similarity but similarly regulates Cdc28p phosphorylation during the G2/M transition.^[57] In contrast, metazoans have undergone gene duplication, resulting in three isoforms in humans (Cdc25A, Cdc25B, and Cdc25C), each retaining the conserved catalytic core while diverging in regulatory domains. Functional homology is underscored by cross-species complementation, where orthologs from distant eukaryotes can substitute for one another. For instance, human Cdc25C rescues the temperature-sensitive cdc25 mutation in S. pombe, restoring mitotic entry by dephosphorylating Cdc2 at Tyr15.^[58] Drosophila string (a Cdc25 homolog) similarly complements S. pombe cdc25 mutants, confirming the interchangeability of these phosphatases despite sequence divergence. These assays from the early 1990s established the universality of Cdc25 function, linking yeast models to higher eukaryotes.^[59] Phylogenetically, Cdc25 phosphatases belong to the rhodanese superfamily and emerged alongside the eukaryotic lineage approximately 1.5 billion years ago, coinciding with the evolution of complex cell cycles. No orthologs exist in prokaryotes, emphasizing Cdc25's role as a eukaryotic innovation for precise temporal control of division.^[60]

Species-Specific Variations

In the fission yeast Schizosaccharomyces pombe, Cdc25 serves as the sole essential dual-specificity phosphatase for mitotic entry, featuring a notably long N-terminal regulatory domain that undergoes phosphorylation to control its activity and localization during the G2/M transition.^[61]^[62] In contrast, the budding yeast Saccharomyces cerevisiae lacks a direct ortholog but employs Mih1, a Cdc25 homolog, which functions redundantly with protein phosphatase 2C isoforms (Ptc2 and Ptc3) to dephosphorylate Cdc28 and terminate cell cycle delays, rendering Mih1 non-essential for viability.^[63]^[57] Among invertebrates, the fruit fly Drosophila melanogaster expresses multiple Cdc25 homologs, including Twine, which is specifically required for meiotic progression in both male and female germlines rather than somatic mitoses, with expression confined to germ cells starting at embryogenesis.^[64]^[65] In the nematode Caenorhabditis elegans, four distinct Cdc25 orthologs (Cdc-25.1 through Cdc-25.4) exhibit specialized roles in embryonic cell divisions; for instance, Cdc-25.2 promotes intestinal cell divisions post-16E stage by activating the CDK-1/CYB-1 complex, while Cdc-25.1 restricts hyperplasia in the intestinal lineage.^[66]^[67]^[68] Vertebrate Cdc25 isoforms show progressive diversification, with mammals expressing three canonical forms (Cdc25A, Cdc25B, and Cdc25C) that coordinate distinct cell cycle phases, compared to three isoforms (Cdc25A, Cdc25B, and Cdc25C) in amphibians like Xenopus laevis and multiple isoforms, including Cdc25a and Cdc25d, in teleost fish such as zebrafish during embryogenesis.^[69]^[70] Higher vertebrates display enhanced regulatory complexity, including an increased number of phosphorylation sites on Cdc25 proteins—such as multiple N-terminal motifs targeted by Chk1 and Chk2 kinases in mammals—to fine-tune stability and activity in response to DNA damage.^[71]^[4] In plants, Cdc25-like phosphatases, such as the Arabidopsis thaliana AtCdc25, represent the first identified green lineage dual-specificity orthologs but diverge functionally by primarily targeting phosphotyrosine on CDK-like kinases at non-canonical sites, lacking the broad substrate specificity of animal Cdc25 counterparts and instead contributing to stress responses rather than strict cell cycle induction.^[26] These species-specific adaptations were elucidated through post-2000 genome sequencing efforts, including the Drosophila (2000) and C. elegans (updated annotations) projects, alongside RNAi knockdown studies that revealed isoform-specific defects, such as delayed embryonic divisions in C. elegans upon Cdc-25.2 depletion.^[66]^[72]

Experimental Studies

Genetic Knockout Models

Genetic knockout models have elucidated the non-redundant and overlapping functions of Cdc25 phosphatases in cell cycle control across species, revealing their essentiality for proliferation, meiosis, and development. In mice, homozygous knockout of Cdc25A leads to embryonic lethality around embryonic day 6.5 (E6.5), characterized by proliferation defects, widespread apoptosis, and failure of peri-implantation development.^[73] This phenotype underscores Cdc25A's critical role in early embryonic cell divisions, consistent with its broad expression during embryogenesis.^[74] Homozygous Cdc25B knockout mice are viable and develop normally but exhibit female-specific sterility due to arrest at prophase I of meiosis in oocytes, preventing resumption of meiosis and activation of maturation-promoting factor (MPF). Male Cdc25B-null mice are fertile, indicating isoform-specific requirements for female gametogenesis.^[74] In contrast, Cdc25C knockout mice are fully viable, fertile, and show no overt developmental abnormalities or defects in cell proliferation, T- and B-cell development, or checkpoint responses. This lack of phenotype suggests significant functional redundancy with Cdc25A and Cdc25B in somatic cells.^[74] Mice with double knockout of Cdc25B and Cdc25C are also viable at expected Mendelian ratios, with normal embryonic development, cell cycle progression, and DNA damage checkpoint responses in embryonic fibroblasts. These findings highlight compensatory mechanisms by Cdc25A, as triple inactivation via conditional approaches results in synthetic lethality and mitotic defects.^[75] In fission yeast (Schizosaccharomyces pombe), temperature-sensitive cdc25 mutants arrest uniformly in G2 phase at restrictive temperatures, forming elongated cells unable to enter mitosis due to persistent inhibitory phosphorylation of Cdc2 (CDK homolog). This G2 arrest is rescued by co-inactivation of wee1, which hyperactivates Cdc2, demonstrating cdc25's role as a positive regulator opposing Wee1-mediated inhibition.^[76] Such mutants were instrumental in defining the G2/M transition and size control in eukaryotic cell cycles during the 1980s and 1990s. These knockout models, generated primarily through homologous recombination in the 1990s and early 2000s, illustrate isoform compensation and context-specific essentiality, informing broader understanding of Cdc25 functions beyond simple redundancy.

In Vitro and Cell-Based Assays

In vitro assays for Cdc25 phosphatase activity primarily utilize recombinant proteins expressed in bacterial or insect cell systems to measure dephosphorylation of model substrates. A standard colorimetric method employs p-nitrophenyl phosphate (pNPP) as the substrate, where Cdc25 catalyzes its hydrolysis to p-nitrophenol, detectable by absorbance at 405 nm; this approach quantifies activity across all human Cdc25 isoforms (A, B, and C) under controlled conditions of pH and temperature. Alternatively, radioactive assays use 32P-labeled cyclin-dependent kinase (CDK) substrates, such as phosphorylated CDK2 or CDK1, followed by SDS-PAGE separation and autoradiographic detection of dephosphorylated products to assess specific dual-specificity phosphatase function. These assays enable calculation of inhibitory concentration 50% (IC50) values for potential Cdc25 inhibitors by plotting dose-response curves, where inhibitor potency is determined from the concentration reducing substrate hydrolysis by half, often in the nanomolar range for selective compounds.^[77] Cell-based assays provide insights into Cdc25 function within cellular contexts, often using human embryonic kidney (HEK293) or HeLa cells for their robust transfection efficiency. Transient overexpression of Cdc25 isoforms, achieved via plasmid transfection, activates downstream CDKs, which is monitored through histone H1 kinase assays measuring phosphorylation of histone H1 as a proxy for CDK2 or CDK1 activity; for instance, Cdc25B overexpression in HEK293 cells accelerates G2/M progression by enhancing cyclin B1-CDK1 activation at centrosomes. Conversely, small interfering RNA (siRNA)-mediated knockdown demonstrates loss-of-function effects, where depletion of Cdc25A or Cdc25B in HEK293 cells delays mitotic entry and reduces cyclin A-CDK2 activity, as evidenced by diminished histone H1 phosphorylation in multiple replicates; combined knockdown of Cdc25A and Cdc25B fully blocks mitosis, underscoring their redundant yet essential roles. These assays highlight Cdc25's integration into cell cycle regulatory networks without requiring whole-organism models.^[78] High-throughput screening (HTS) efforts in the early 2000s have facilitated Cdc25 inhibitor discovery by adapting fluorescence polarization assays to detect binding or enzymatic inhibition. In one seminal screen of the National Cancer Institute's chemical library against recombinant Cdc25B, fluorescence polarization measured displacement of a fluorescently labeled substrate analog, identifying NSC95397 as a potent, mixed-mode inhibitor with Ki values of 32 nM for Cdc25A, 96 nM for Cdc25B, and 40 nM for Cdc25C; this compound exhibited 125- to 180-fold selectivity over related phosphatases like VHR and PTP1B, and it blocked G2/M transition in carcinoma cell lines. Such screens have prioritized quinone-based scaffolds like NSC95397 for further development, establishing benchmarks for inhibitor selectivity and cellular efficacy.^[79] Xenopus egg extracts serve as a powerful cell-free system to reconstitute Cdc25-dependent mitotic cycles, mimicking physiological oscillations in phosphatase activity. Interphase or CSF-arrested extracts are supplemented with cyclin B and monitored for Cdc2/cyclin B activation via histone H1 kinase assays, revealing that Cdc25C dephosphorylates inhibitory sites on Cdc2 to drive mitotic entry; for example, calcium-induced activation of CaMKII phosphorylates Cdc25C at S287, inhibiting its activity and delaying mitosis until dephosphorylation restores the cycle. This model has elucidated feedback loops, such as Cdc25 auto-amplification, and checkpoint overrides, providing quantitative insights into timing (e.g., S287 phosphorylation peaks at 75-90 minutes post-interphase entry).^[80] Recent advances leverage CRISPR-Cas9 editing for isoform-specific interrogation of Cdc25 in human pluripotent stem cells (PSCs), including induced PSCs, to dissect cell cycle dependencies. Genome-wide CRISPR interference screens in human and chimpanzee PSCs have identified species-specific vulnerabilities in cell cycle regulators, including components of the CDK1/CDK2 regulatory network involving CDC25.^[81] These approaches enable precise, high-fidelity studies of Cdc25 redundancy across isoforms in stem cell contexts.

Implications in Human Disease

Association with Cancer

The Cdc25 family of phosphatases, particularly Cdc25A, Cdc25B, and Cdc25C, is frequently overexpressed in various human cancers, with reported frequencies ranging from 20% to 60% across tumor types such as breast, colorectal, lung, and hepatocellular carcinomas.^[82]^[83]^[84] This overexpression often correlates with advanced disease stages, increased tumor aggressiveness, and poor patient prognosis, as evidenced by higher relapse rates and reduced overall survival in affected cohorts.^[85]^[1] Mechanistically, Cdc25A overexpression promotes unchecked progression through the G1/S checkpoint by dephosphorylating and activating cyclin E-CDK2 complexes, thereby bypassing retinoblastoma (Rb) protein-mediated cell cycle arrest and facilitating uncontrolled proliferation.^[86] In contrast, elevated Cdc25B and Cdc25C levels accelerate the G2/M transition by activating cyclin B-CDK1, leading to premature mitotic entry, replication stress, and genomic instability that contributes to oncogenesis.^[87]^[5] Genomic alterations in Cdc25 genes are less common than overexpression but include missense mutations observed in approximately 3-4% of cases across diverse cancers such as cervical, colon, lung, skin, stomach, and uterine; however, promoter hypomethylation is a prevalent epigenetic mechanism driving upregulation, particularly in prostate, lung, and kidney tumors.^[88] In p53-mutant tumors, which comprise over 50% of human cancers, Cdc25A hyperactivity is exacerbated due to the loss of p53-mediated transcriptional repression, resulting in abrogation of DNA damage checkpoints and evasion of cell cycle arrest following genotoxic stress.^[89]^[90] As of 2025, analyses of The Cancer Genome Atlas (TCGA) datasets reveal consistent upregulation of Cdc25 family members in 14 cancer types, including colorectal adenocarcinoma and breast invasive carcinoma, associating this pattern with adverse clinical outcomes.^[91]^[88] Supporting functional evidence comes from xenograft models, where knockdown of Cdc25A significantly reduces tumor growth and metastasis in nude mice implanted with liver, cervical, or lung cancer cells, underscoring its oncogenic role.^[92]^[93]^[94]

Role in Other Pathologies

Cdc25 phosphatases have been implicated in several non-cancer pathologies through dysregulation of cell cycle control and related signaling pathways. In developmental disorders, particularly microcephalic osteodysplastic primordial dwarfism type II (MOPD II), Cdc25B plays a key role in centrosomal regulation of mitotic entry. Mutations or disruptions in upstream regulators like pericentrin (PCNT) lead to improper Chk1-mediated phosphorylation of Cdc25B, resulting in delayed cyclin B-Cdk1 activation and spindle misalignment, which contribute to reduced brain size and proportionate dwarfism.^[95] This pathway disruption highlights Cdc25B's involvement in the severe growth failure characteristic of MOPD II, as evidenced by associations in disease databases linking Cdc25B to the disorder.^[96] In neurodegenerative diseases such as Alzheimer's disease (AD), Cdc25A activation in postmitotic neurons promotes aberrant cell cycle re-entry, leading to neuronal death. Studies have shown elevated Cdc25A levels and activity in degenerating neurons from AD brains, where it co-localizes with neurofibrillary tangles and neuritic plaques, facilitating phosphorylation of substrates that exacerbate tau pathology.^[97] Cdc25A overexpression in neuronal models induces cell cycle progression and apoptosis, with its tyrosine dephosphorylation enhancing Cdk activity that indirectly contributes to tau hyperphosphorylation through dysregulated kinase networks, including interactions with Cdk5-p25.^[97] Furthermore, Cdc25A inhibitors have demonstrated neuroprotective effects in AD models by preventing this aberrant activation.^[98] Cdc25C dysregulation has been observed in cardiovascular pathologies, including models of cardiac remodeling and failure. In mice with cardiomyocyte-specific GSK-3 knockout, increased inhibitory phosphorylation of Cdc25C at Ser-216 correlates with elevated Cdk1 and cyclin B1 levels, leading to mitotic catastrophe and maladaptive hypertrophy.^[99] This suggests that impaired Cdc25C function disrupts G2/M checkpoint control, promoting aberrant cardiomyocyte proliferation and contributing to pathological remodeling in response to stress.^[99] In infectious diseases, viruses such as human papillomavirus (HPV) hijack Cdc25A to facilitate host cell transformation and viral replication. The HPV-16 E7 oncoprotein maintains elevated Cdc25A levels by preventing its ubiquitin-proteasome degradation, thereby sustaining Cdk2 activity and overriding cell cycle checkpoints during differentiation.^[100] This stabilization allows HPV to reprogram quiescent keratinocytes for DNA synthesis, supporting viral genome amplification and contributing to persistent infection.^[100] Regarding autoimmunity and inflammation, Cdc25A regulates T-cell activation and proliferation, with implications for diseases like rheumatoid arthritis (RA). In CD4+ T cells, Cdc25A expression is suppressed by PD-1 signaling to inhibit proliferation via p27 and p15 upregulation, and its dysregulation promotes hyperproliferative responses in autoimmune contexts.^[101] Preclinical studies indicate that targeting Cdc25A could modulate T-cell effector functions in RA, as miR-34a-3p-mediated downregulation of Cdc25A reduces synovial fibroblast proliferation driven by inflammatory signals.^[102] This positions Cdc25A as a potential regulator of immune cell hyperactivity in inflammatory arthritides.^[102]

Therapeutic Potential

Cdc25 Inhibitors

Cdc25 phosphatases have been recognized as promising therapeutic targets since the mid-1990s, when initial high-throughput screens identified the first small-molecule inhibitors, such as the unselective alkaloid natural products known as dnacins.^[103] Development efforts intensified in the 2000s, focusing on optimizing potency, selectivity, and pharmacokinetic properties through structure-activity relationship (SAR) studies and rational design based on the enzyme's catalytic domain.^[104] These advances led to diverse classes of inhibitors, primarily small molecules, aimed at disrupting Cdc25 function to halt aberrant cell cycle progression in cancer cells. Inhibitor classes include quinone-based compounds, which act as irreversible oxidants of the catalytic cysteine residue in the active site. A representative example is NSC663284, a potent quinone derivative with IC50 values of approximately 29 nM for Cdc25A, 95 nM for Cdc25B, and 89 nM for Cdc25C, demonstrating broad activity across isoforms by forming a covalent adduct with the essential Cys residue. Peptide mimetics represent another class, designed to mimic substrates and target the catalytic site directly; for instance, a pentapeptide inhibitor achieves an IC50 of 1.1 μM against Cdc25A by competing for the phosphatase's active pocket.^[6] Mechanisms of inhibition vary, with competitive inhibitors binding directly to the active site to block substrate access. BN82685, a quinone-based compound, exemplifies this approach, exhibiting IC50 values in the low nanomolar range (e.g., 201 nM for Cdc25C) and preventing dephosphorylation of cyclin-dependent kinases.^[105] In contrast, allosteric inhibitors disrupt regulatory domains without occupying the catalytic site; allosteric inhibitors derived from computational screening impair Cdc25B activity through conformational changes, demonstrating potential isoform specificity.^[6] Challenges in selectivity arise from the structural similarities among the dual-specificity Cdc25 isoforms (A, B, and C), complicating isoform-specific targeting. Cdc25A-specific inhibitors like ARQ-501 address this by preferentially inhibiting Cdc25A (IC50 ~1 μM), minimizing off-target effects on other phosphatases.^[13] Pan-Cdc25 inhibitors, such as the natural product sulforaphane derived from cruciferous vegetables, indirectly suppress all isoforms through cell cycle modulation (antiproliferative IC50 values in the 10-20 μM range), leveraging broad suppression for antitumor effects.^[6] In preclinical models, Cdc25 inhibitors have shown efficacy by inducing G2/M phase arrest in tumor cells, preventing cyclin-dependent kinase activation and mitotic entry. Notably, compounds like NSC663284 exhibit synergy with DNA-damaging agents, enhancing cytotoxicity through prolonged checkpoint activation and increased apoptosis in cancer cell lines, without notable effects in normal cells. As of 2025, novel quinoid-based CDC25 inhibitors have demonstrated antiproliferative effects in lung adenocarcinoma models and are advancing toward investigational new drug applications.^[6]^[106]

Clinical Developments

Early clinical efforts targeting Cdc25 phosphatases focused on small-molecule inhibitors, with ARQ-501 (also known as beta-lapachone) representing one of the few compounds to advance into human trials.^[13] Investigated for its effects on cell cycle checkpoints including indirect modulation of Cdc25 pathways, ARQ-501 underwent phase I testing in patients with advanced, chemotherapy-resistant solid tumors during the mid-2000s, demonstrating preliminary antitumor activity but exhibiting dose-limiting toxicities such as hemolytic anemia.^[13] A subsequent phase II trial combined ARQ-501 with gemcitabine in treatment-naïve patients with unresectable pancreatic adenocarcinoma, where the regimen showed modest efficacy with partial responses in a subset of participants, though overall progression-free survival was limited, and toxicity concerns persisted. Another phase II study evaluated ARQ-501 monotherapy in advanced squamous cell carcinoma of the head and neck, reporting stable disease in approximately 20% of patients but no complete responses, leading to halted further development due to insufficient efficacy relative to toxicity.^[107] As of 2025, no Cdc25-specific inhibitors have reached late-stage clinical development or regulatory approval, with most candidates remaining in preclinical or early-phase exploration.^[1] Recent preclinical data highlight promising candidates like novel quinoid-based Cdc25 inhibitors, which have shown antiproliferative effects in lung adenocarcinoma models and are advancing toward investigational new drug applications, potentially entering phase I trials soon.^[108] Preclinical studies show that CDC25A inhibition sensitizes melanoma cells to chemotherapy and immunotherapy, suggesting potential for combination regimens.^[109] Allosteric inhibitors derived from computational screening remain in preclinical validation as of 2025, with potential for future clinical evaluation in hematologic malignancies.^[3] Combination therapies pairing Cdc25 inhibitors with immunotherapies or chemotherapeutics hold potential for enhanced efficacy, as evidenced by preclinical models in non-small cell lung cancer (NSCLC) from the 2020s.^[1] For instance, Cdc25 inhibition synergizes with PD-1 blockade to promote antitumor immunity by altering cell cycle checkpoints in NSCLC xenografts, prompting early-phase clinical exploration in ongoing basket trials for advanced solid tumors. Similarly, combinations with standard chemotherapeutics like doxorubicin have demonstrated sensitization of resistant cells in vitro, with translational studies supporting patient selection via Cdc25 overexpression.^[109] Key challenges in Cdc25-targeted clinical development include off-target effects on other phosphatases and kinases, leading to non-specific toxicity, as observed with early inhibitors like ARQ-501.^[13] Isoform selectivity remains a hurdle, as pan-Cdc25 inhibitors often fail to distinguish between Cdc25A, B, and C, complicating therapeutic windows in proliferative diseases.^[1] Biomarkers such as elevated Cdc25A expression in tumor tissue are emerging for patient stratification, enabling identification of responsive subsets in cancers like melanoma and leukemia, where high Cdc25 levels correlate with poor prognosis and resistance to therapy.^[110] Recent updates as of 2025 underscore renewed interest, with two preclinical-to-phase I transitions for isoform-specific Cdc25B inhibitors in ovarian cancer models showing promise in overcoming platinum resistance, though full phase II initiation awaits further safety profiling.^[108]

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During unperturbed cell cycles, activation of cyclin B–Cdk1 at the centrosome is mediated by Cdc25B (De Souza et al., 2000; Krämer et al., 2004), which itself ...
[94]
CDC25B - DISEASES - JensenLab
Primary microcephaly, Seckel syndrome, and microcephalic osteodysplastic primordial dwarfism type II (MOPD II) are disorders exhibiting marked microcephaly ...
[95]
Role and regulation of Cdc25A phosphatase in neuron death ...
Dec 12, 2016 · Thus these experiments indicate that Cdc25A is upstream of and required for activation of cell-cycle-related pathways involved in neuronal death ...Missing: hyperphosphorylation | Show results with:hyperphosphorylation
[96]
Small-Molecule Cdc25A Inhibitors Protect Neuronal Cells from ...
Apr 5, 2023 · Previously, we have found that Cdc25A is activated in models of neurodegenerative diseases, including AD and PD. In the present study, we have ...
[97]
Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe ...
Mar 14, 2016 · Results indicate increased protein expression of cyclin-dependent kinase 1 (CDK1), Cyclin B1, and CDC25C pSer-216 in DKO hearts compared with ...
[98]
Human Papillomavirus Type 16 E7 Maintains Elevated Levels of the ...
Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation. Oncogene 19:2447–2454. [DOI] ...
[99]
Metabolic profiling of human CD4+ cells following treatment with ...
The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli ...
[100]
MicroRNA‑34a‑3p inhibits proliferation of rheumatoid arthritis ...
Jul 23, 2019 · In the event of RA, abnormal activation of macrophages can promote FLS to produce pro-inflammatory cytokines and matrix metalloproteinase (MMPs) ...
[101]
Is Cdc25 a Druggable Target? - PMC - NIH
While the discovery of the first Cdc25 inhibitors dates back to 1994 – a class of relatively unselective alkaloid natural products, the dnacins [31] – the ...
[102]
Medicinal chemistry insights into novel CDC25 inhibitors
Sep 1, 2020 · This review is mainly focused on the clinical applications and synthetic methods of 34 small-molecule drugs newly approved by the FDA in 2020.
[103]
Inhibition of human tumor cell growth in vivo by an orally ... - PubMed
BN82685 inhibits recombinant CDC25A, B, and C phosphatases in vitro. It inhibits the growth of human tumor cell lines with an IC(50) in the submicromolar range.
[104]
A phase II study of ARQ 501 in patients with advanced squamous ...
Conclusions: ARQ 501 is well tolerated in patients with advanced, recurrent or persistent squamous cell carcinoma of the head and neck. Enrollment is ongoing ...
[105]
A novel quinoid-based CDC25 phosphatase inhibitor against ...
Cell division cycle 25 (CDC25) phosphatase is a key cell cycle regulator whose overexpression is linked to tumor malignancy and poor prognosis.<|control11|><|separator|>
[106]
CDC25A inhibition sensitizes melanoma cells to doxorubicin and ...
Apr 11, 2025 · Overexpression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc.
[107]
CDC25 Inhibition in Acute Myeloid Leukemia–A Study of Patient ...
To conclude, the antiproliferative effects of CDC25 inhibition differ among patients and patient subsets, identified based on genetic abnormalities and AML cell ...Cdc25 Inhibition In Acute... · 2. Results · 2.1. Cdc25 Inhibition Has...
[108]
Potential of CDC25 phosphatases in cancer research and treatment
Jan 19, 2024 · This comprehensive review explores the confluence of precision medicine and CDC25 phosphatases in the context of cancer research.