CDC25A (Cell division cycle 25A)

2015-08-01   Christine Dozier , Stéphane Manenti 

Identity

HGNC
LOCATION
3p21.31
LOCUSID
ALIAS
CDC25A2
FUSION GENES

Abstract

CDC25A phosphatase is essential for cell cycle progression by activating the cyclin-associated kinases CDK4\/6, CDK2 and CDK1. Its invalidation in mice is embryonic lethal. Its expression is tigthtly regulated at many levels and its overexpression is observed in various cancers, often associated with high grade tumors and poor prognosis.

DNA/RNA

Atlas Image
Genomic organization of human CDC25A gene on chromosome 3 p-ter.

Description

CDC25A is about 31.13 Kb located on the short (p) arm of chromosome 3, in the centromere-to-telomere orientation. The gene has 15 exons and the start codon is located at the end of exon 1 and stop codon in the beginning of exon 15.

Transcription

The CDC25A transcript is 3704 bp in length. So far two major transcript variant have been reported, CDC25A1 and A2. The transcript variant CDC25A2, has a deletion of 120 nucleotides (exon 6) resulting in a protein having truncation of 40 amino acids (between amino acid 160-201). However, both the N-terminal and C-terminal end of the protein is the same in both splice variant.

Proteins

Atlas Image
Domains of different isoforms of CDC25A (A1 and A2). The splice variant A2 lacks an in-frame exon (exon 6) encoding 40 amino acids (amino acid 160-201), however, has the same N- and C-termini compared to isoform A1. The approx. molecular weight of each isoform is mentioned in parenthesis.

Description

The full length CDC25A protein consists of 524 amino acids with an estimated molecular weight of 59 kDa. The other reported isoform CDC25A2, consists of 484 amino acids with a molecular weight of 54.4 kDa (Wegener et al., 2000).. Both the isoforms have the same N- and C-terminal end, thus expected to have similar catalytic activity. The N-terminal regulatory domain contains several phosphorylation sites and shows low sequence homology between CDC25 family members, whereas C-terminal end has conserved Rhodanese homology domain containing the active site cysteine. The catalytic site contain the CX5R motif (C= cysteine; X= any amino acid; R= arginine) common to all protein tyrosine phosphatases (Boutros et al., 2006). Upon apoptosis induction, CDC25A is cleaved at D223 (D=Aspartic acid) by caspase to generate a catalytically active CDC25A C-terminal 37Kda protein (Mazars et al., 2009; Chou et al., 2010).

Expression

CDC25A is expressed early during embryonic stages and in adults it is expressed in a variety of normal cells and tissues. CDC25A is a highly expressed gene in a variety of human cancers including breast, esophageal, gastric, lung, thyroid, head and neck cancers and also in high grade lymphomas.

Localisation

CDC25A initially believed to be a nuclear protein. But using fluorescence loss in photobleaching (FLIP) a more dynamic nuclear-cytosolic shuttling of CDC25A localization has been reported. At the very N-terminus end between amino acid 38-59, the nuclear export sequence (NES) is located, whereas between amino acid 272-294, a bipartite nuclear localization signal (NLS) was proved to be important for its nuclear localization (Källström et al., 2005). Depending of the cell line, CDC25A is nuclear or nuclear and cytoplasmic.

Function

- CDC25A is essential for early embryonic development as Cdc25A-null mice die in utero by embryonic day 7(Ray et al., 2007).
- It is a member of the M-phase inducer (MPI) phosphatase family protein, which not only regulates mitotic progression by activating mitotic CDKs in a dosage-dependent manner, it is also equally important in G1 and for G1 to S-phase transition.
- During G1, CDC25A dephosphorylates CDK4/CDK6 on tyrosine 17 and 24, respectively, allowing their association with D-type cyclins and thus their activation (Bertero et al., 2013). During G1 to S transition, it activates CDK2 by removing two inhibitory phosphates on residues threonine 14 and tyrosine 15. During G2/M transition CDC25A similarly regulates the activity of CDK1 (CDC2).
- It is an inhibitor of apoptosis by inhibiting apoptosis signal-regulating kinase 1 (ASK1). in a phosphatase-independent manner, by activating the AKT-survival pathway in the cytoplasm and also by stimulating NF-kB activity through NFKBIA (IκB- α) destabilization (review Fernandez-Vidal et al., 2008; review Shen and Huang, 2012; Hong et al., 2012). But overexpressed nuclear CDC25A also exhibits pro apoptotic activity by activating the pro-apoptotic factor FKHLR1 (review Fernandez-Vidal et al., 2008; review Shen and Huang, 2012).
- CDC25A plays an important role in spermatogenesis as decreased transcript level of Cdc25A is correlated with spermatogenic failure and failed sperm retrieval in infertile men. (Cheng et al., 2009).
-CDC25A also plays a role in meiotic maturation of oocytes, its activity is required for the metaphase II arrest in mouse oocytes (Oh et al., 2013).
- CDC25A was shown to function as a androgen receptor corepressor in prostate cancer cells (Chiu et al., 2009).
Regulation
- CDC25A is transcriptionally regulated by E2F, a transcription factor implicated at the G1/S transition, c-myc, STAT3, the p53-pathway via the transcription factor ATF3, TCF/beta-catenin, FOXM1, NANOG in embryonic stem cell and PROX1 in neural precursor (review Fernandez-Vidal et al., 2008; review Shen and Huang, 2012).
- CDC25A is also regulated at the translational level by the translation initiation factors EIF2S1 (eIF2alpha), EIF3M, the RNA-binding proteins BOLL in spermatogenesis, and various miRNAs such as let7b, 15a, 21, 449a, 449b, 483-3p, 424/503 cluster and 141-3p. Some of these miRNAs being deregulated in cancers can contribute to the overexpression of CDC25A in cancers.
- CDC25A activity can be regulated by phosphorylation events (review Fernandez-Vidal et al., 2008; review Shen and Huang, 2012). The kinases PIM-1, RAF1, CDK2, RSK, ROCK1 (p160Rock) and the phosphatase CDC14B have been shown to regulate CDC25A activity. The kinase CHK1 has been shown to phosphorylate CDC25A on serine 178 and threonine 507 preventing its interaction with its CDK/cyclin substrates.
- CDC25A is an unstable protein in interphase, or under several different stress conditions (DNA damage induced by ionizing radiation, ultraviolet light, replicative stress) being degraded by the proteasome after ubiquitination by SCFβTrCP E3 ubiquitin ligase. This ubiquitination is dependent on several phosphorylation events in the N-terminal part of the protein carried out by many kinases such as CHK1 (on serine 76, 124, 178, 279 and 293), CHK2 (on serine 124, 178 and 293), p38MAPK (on serine 76), GSK3-β (on serine 76), Plk3 (on threonine 80), NEK11 (on serine 82 and 88) and CK1alpha and epsilon (on serine 82) (review Fernandez-Vidal et al., 2008; review Shen and Huang, 2012).
- CDC25A protein is stabilized during mitosis due to phosphorylation on serine 18 and 116 by CDK1/cyclinB occuring at the G2/M transition (Mailand et al., 2002). At the mitotic exit and in early G1, CDC25A is degraded by the proteasome after ubiquitination by the E3 ubiquitine ligase APC/C (cyclosome) (review Fernandez-Vidal et al., 2008; review Shen and Huang, 2012).
- CDC25A protein level is important for oncogene-induced transformation and mouse mammary tumor virus (MMTV)-neu/ras induced mammary tumorigenesis (Ray et al., 2007).
- During early cell cycle progression glycogen synthase kinase 3-beta (GSK-3β) can phosphorylate allowing its proteasomal degradation. Interestingly, the same report showed that overproduction of CDC25A in some human cancers is correlated to the inactivation of GSK-3β (Kang et al., 2008).
- Overexpression of CDC25A in some human sarcomas has also been shown to be the result of transcriptional upregulation involving the transcription factor TCF/β-catenin upregulated upon activation of the wnt canonical signaling (Vijayakumar et al.,2011). HOMOLOGY CDC25A gene is highly conserved among mammals (99% homology with Chimpanzee; 90% with dog; about 86% with rat and about 85% with mouse). In mammals, CDC25A has two orthologs, CDC25B and CDC25C. Among them, the N-terminal regulatory region show low sequence homology (20-25% identity), however, the C-terminal catalytic region is quite conserved with about 64% homology with CDC25B and about 58% homology to CDC25C.

Mutations

Note

Gene mutation or amplification is not commonly reported for CDC25A. A naturally occurring point mutation (C to A) of mouse Cdc25A gene has been reported where Histidine 128 (CAC) has been converted to Glutamine (CAA). This change caused an increase in CDC25A phosphatase activity and thereby affected erythropoiesis in mice only under certain genetic background (Melkun et al., 2002). A human polymorphism variant in which Serine 88 is converted to Phenylalanine has been described. This variant fails to interact with ASK1 and therefore does not suppress ASK1-mediated apoptosis, which leads to early embryonic lethality in mice and predisposes to cancer in human (Bahassi et al. 2011)..

Implicated in

Entity name
Breast cancer
Note
- In about 47% of early (T1) stage breast cancer patients CDC25A is reported to be overexpressed.
- In some breast cancer cell lines it was reported that CDC25A overexpression is mainly due to increased protein stability as oppose to gene amplification or transcriptional upregulation. (Löffler et al., 2003). In a subset of human breast cancers overexpression of the ubiquitin hydrolase DUB3, which deubiquitinates CDC25A preventing its degradation, is shown to be responsible for overexpression of CDC25A (Pereg et al., 2010).
- In mice, overexpression of CDC25A alone in mammary gland using mouse mammary tumor virus (MMTV) promoter, is not sufficient to induce mammary tumorigenesis. However, such mammary specific overexpression of CDC25A does cooperate with HER2/neu-ras signaling to form more aggressive tumors with enhanced genomic instability. (Ray et al., 2007).
- In contrast, hemizygous loss of Cdc25A in mice protected them significantly from MMTV-neu/ras-induced mammary tumorigenesis, possibly by restricting precancerous cell proliferation and also by enhancing G2-checkpoint response. Thus the protein level of CDC25A is crucial for the initiation and/or progression of breast tumorigenesis in mice (Ray and Kiyokawa, 2007).
Prognosis
Overexpression of CDC25A is correlated with more aggressive breast cancer with poor prognosis.
Cytogenetics
CDC25A overexpression in MMTV-CDC25A; MMTV-neu double transgenic mice caused faster tumor growth as compared to MMTV-neu single transgenic mice. Importantly, such CDC25A overexpressing tumor cells displayed miscoordination of S phase and mitosis, and had severe genomic instability as evidenced by aneuploidy and deletion of fragile chromosomal regions (e.g., telomeric region of chromosome 4, which is homologous to human chromosome 1p31-36, a hotspot for several human cancers including breast cancer).
Entity name
Hepatocellular carcinoma
Note
Overexpression of CDC25A mRNAs was found in 69% of hepatocellular carcinomas (HCCs) and this overexpression was also confirmed by Immunohistochemistry (56% HCCs exhibit overexpression of CDC25A) and western blot analysis (Xu et al., 2003). Different CDC25 inhibitor (such as vitamin K analog Cpd 5; phenyl maleimide compound PM-20; 2-Methoxyestadiol, a physiological metabolite of estrogen) are capable of inhibiting the hepatocellular carcinoma growth both in vitro and in vivo (Wang et al., 2001; Kar et al, 2006).
Disease
High expression of CDC25A was associated with dedifferentiated phenotype and portal vein invasion.
Prognosis
CDC25A overexpression is associated with poor prognosis of hepatocellular carcinoma.
Entity name
Retinoblastoma
Note
Overexpression of CDC25A mRNAs was found in 48,33 % retinoblastomas, confirmed by immunohistochemistry (52,29 %) and western blotting (Shingh et al., 2014).
Prognosis
Expression of CDC25A showed significant correlation with poor tumour differentiation and tumour invasion.
Entity name
Non-Hodgkins lymphoma
Prognosis
High level of CDC25A mRNAs was found in 35 % of the tumors and were more frequently observed in aggressive than in indolent lymphomas. This was also confirmed at the protein level.
Entity name
Gastric cancer
Note
By immunohistochemistry CDC25A was found expressed in 87.1 % of gastric carcinomas, correlated with c-myc overexpression (Xing et al., 2008).
Disease
Overexpression of CDC25A was independent of intestinal or diffuse type of gastric cancer.
Prognosis
Association between CDC25A expression and higher histological grade of differentiation.

Bibliography

Pubmed IDLast YearTitleAuthors
213100582011A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis.Bahassi el M et al
116981912001Mammalian G1- and S-phase checkpoints in response to DNA damage.Bartek J et al
234292622013CDC25A targeting by miR-483-3p decreases CCND-CDK4/6 assembly and contributes to cell cycle arrest.Bertero T et al
164881262006The when and wheres of CDC25 phosphatases.Boutros R et al
175687902007CDC25 phosphatases in cancer cells: key players? Good targets?Boutros R et al
228997142012Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death.Chang KH et al
167206232006Association of spermatogenic failure with decreased CDC25A expression in infertile men.Cheng YS et al
190131802009CDC25A functions as a novel Ar corepressor in prostate cancer cells.Chiu YT et al
203683352010Pro-apoptotic role of Cdc25A: activation of cyclin B1/Cdc2 by the Cdc25A C-terminal domain.Chou ST et al
82764021993Chromosome mapping of human CDC25A and CDC25B phosphatases.Demetrick DJ et al
193051442009Upregulation of the CDC25A phosphatase down-stream of the NPM/ALK oncogene participates to anaplastic large cell lymphoma enhanced proliferation.Fernandez-Vidal A et al
18369781991Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins.Galaktionov K et al
220655972012The cell cycle regulator CDC25A is a target for JAK2V617F oncogene.Gautier EF et al
224178282012Cdc25A promotes cell survival by stimulating NF-κB activity through IκB-α phosphorylation and destabilization.Hong HY et al
155720302005Cdc25A localisation and shuttling: characterisation of sequences mediating nuclear export and import.Källström H et al
181673382008GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers.Kang T et al
1824635020082-Methoxyestradiol inhibits hepatocellular carcinoma cell growth by inhibiting Cdc25 and inducing cell cycle arrest and apoptosis.Kar S et al
146032472003Distinct modes of deregulation of the proto-oncogenic Cdc25A phosphatase in human breast cancer cell lines.Löffler H et al
108279532000Rapid destruction of human Cdc25A in response to DNA damage.Mailand N et al
124115082002Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability.Mailand N et al
189275892009A caspase-dependent cleavage of CDC25A generates an active fragment activating cyclin-dependent kinase 2 during apoptosis.Mazars A et al
124113232002A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is associated with altered cell-cycle status of early erythroid progenitor cells.Melkun E et al
233453982013Cdc25A activity is required for the metaphase II arrest in mouse oocytes.Oh JS et al
202288082010Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A.Pereg Y et al
180735362007CDC25A levels determine the balance of proliferation and checkpoint response.Ray D et al
176388702007Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice.Ray D et al
222637972012The role of Cdc25A in the regulation of cell proliferation and apoptosis.Shen T et al
253265182015Expression of CDC25A and CDC25B phosphatase proteins in human retinoblastoma and its correlation with clinicopathological parameters.Singh L et al
215758612011High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/β-catenin target gene, CDC25A.Vijayakumar S et al
115857572001Involvement of Cdc25A phosphatase in Hep3B hepatoma cell growth inhibition induced by novel K vitamin analogs.Wang Z et al
111391442000Alternative splicing in the regulatory region of the human phosphatases CDC25A and CDC25C.Wegener S et al
179348312008Expression of CDC25 phosphatases in human gastric cancer.Xing X et al
127387322003Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas.Xu X et al
114161552001The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1.Zou X et al

Other Information

Locus ID:

NCBI: 993
MIM: 116947
HGNC: 1725
Ensembl: ENSG00000164045

Variants:

dbSNP: 993
ClinVar: 993
TCGA: ENSG00000164045
COSMIC: CDC25A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000164045ENST00000302506P30304
ENSG00000164045ENST00000302506A0A024R2S4
ENSG00000164045ENST00000351231P30304
ENSG00000164045ENST00000351231A0A024R2R6
ENSG00000164045ENST00000437972C9JH94
ENSG00000164045ENST00000443342C9JFR5

Expression (GTEx)

0
5
10
15
20
25

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
Progesterone-mediated oocyte maturationKEGGko04914
Cell cycleKEGGhsa04110
Progesterone-mediated oocyte maturationKEGGhsa04914
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
DNA damage-induced cell cycle checkpointsKEGGhsa_M00691
DNA damage-induced cell cycle checkpointsKEGGM00691
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
DiseaseREACTOMER-HSA-1643685
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G1/S DNA Damage CheckpointsREACTOMER-HSA-69615
p53-Independent G1/S DNA damage checkpointREACTOMER-HSA-69613
p53-Independent DNA Damage ResponseREACTOMER-HSA-69610
Ubiquitin Mediated Degradation of Phosphorylated Cdc25AREACTOMER-HSA-69601
G2/M CheckpointsREACTOMER-HSA-69481
Activation of ATR in response to replication stressREACTOMER-HSA-176187
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G0 and Early G1REACTOMER-HSA-1538133
G1/S TransitionREACTOMER-HSA-69206
Cyclin E associated events during G1/S transitionREACTOMER-HSA-69202
G1/S-Specific TranscriptionREACTOMER-HSA-69205
E2F mediated regulation of DNA replicationREACTOMER-HSA-113510
E2F-enabled inhibition of pre-replication complex formationREACTOMER-HSA-113507
S PhaseREACTOMER-HSA-69242
Cyclin A:Cdk2-associated events at S phase entryREACTOMER-HSA-69656
Mitotic G2-G2/M phasesREACTOMER-HSA-453274
G2/M TransitionREACTOMER-HSA-69275
Cyclin A/B1 associated events during G2/M transitionREACTOMER-HSA-69273
Cyclin B2 mediated eventsREACTOMER-HSA-157881
Polo-like kinase mediated eventsREACTOMER-HSA-156711
DeubiquitinationREACTOMER-HSA-5688426
Ub-specific processing proteasesREACTOMER-HSA-5689880
Neurodegenerative DiseasesREACTOMER-HSA-8863678
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease modelsREACTOMER-HSA-8862803

References

Pubmed IDYearTitleCitations
146033232003Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage.182
126765832003Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A.176
123995442002Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints.140
126769252003Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents.97
198337672009miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A.97
204629532010MiR-322/424 and -503 are induced during muscle differentiation and promote cell cycle quiescence and differentiation by down-regulation of Cdc25A.93
124115082002Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability.87
181673382008GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers.84
122349272002Dual mode of degradation of Cdc25 A phosphatase.72
145599972003Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding.62

Citation

Christine Dozier ; Stéphane Manenti

CDC25A (Cell division cycle 25A)

Atlas Genet Cytogenet Oncol Haematol. 2015-08-01

Online version: http://atlasgeneticsoncology.org/gene/40004/cdc25a-(cell-division-cycle-25a)

Historical Card

2008-02-01 CDC25A (Cell division cycle 25A) by  Dipankar Ray,Hiroaki Kiyokawa 

Dept. of Mol. Pharmacol & Biol. Chem, Northwestern University, Chicago, IL 60611, USA (DR, HK); Robert H. Lurie Compre. Cancer Center, Northwestern University, Chicago, IL 60611, USA (HK)