HGNC Approved Gene Symbol: CDC25A
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:48,157,146-48,188,417 (from NCBI)
The cell division cycle 25 (CDC25) family of proteins are highly conserved dual specificity phosphatases that activate cyclin-dependent kinase (CDK) complexes, which in turn regulate progression through the cell division cycle. CDC25 phosphatases are also key components of the checkpoint pathways that become activated in the event of DNA damage. In mammalian cells, 3 isoforms have been identified: CDC25A, CDC25B (116949), and CDC25C (157680). CDC25A mainly activates the CDK2 (116953)-cyclin E (123837) and CDK2-cyclin A (123835) complexes during the G1-S transition, but also has a role during the G2-M transition by activating CDK1 (116940)-cyclin B (123836) complexes, which are thought to initiate chromosome condensation (summary by Boutros et al., 2007).
Galaktionov and Beach (1991) cloned a cDNA corresponding to the human CDC25A gene from a teratocarcinoma library.
Galaktionov et al. (1995) showed that in rodent cells, human CDC25A or CDC25B but not CDC25C phosphatases cooperate with either the gly12-to-val mutation of the HRAS gene (190020.0001) or loss of RB1 (614041) in oncogenic focus formation. The transformants were highly aneuploid, grew in soft agar, and formed high-grade tumors in nude mice. Overexpression of CDC25B was detected in 32% of human primary breast cancers tested.
To protect genome integrity and ensure survival, eukaryotic cells exposed to genotoxic stress cease proliferating to provide time for DNA repair. Mailand et al. (2000) demonstrated that human cells respond to ultraviolet light or ionizing radiation by rapid, ubiquitin- and proteasome-dependent protein degradation of CDC25A, a phosphatase that is required for progression from G1 to S phase of the cell cycle. This response involved activated CHK1 protein kinase (603078) but not the p53 (191170) pathway, and the persisting inhibitory tyrosine phosphorylation of CDK2 (116953) blocked entry into S phase and DNA replication. CDC25A-dependent cell cycle arrest occurs 1 to 2 hours after ultraviolet radiation, whereas the p53-p21 axis affects the cell cycle only several hours after ultraviolet treatment. Mailand et al. (2000) thus concluded that the checkpoint response to DNA damage occurs in 2 waves. Overexpression of CDC25A bypassed the mechanism of cell cycle arrest, leading to enhanced DNA damage and decreased cell survival. Mailand et al. (2000) concluded that the results identified specific degradation of CDC25A as part of the DNA damage checkpoint mechanism and suggested how CDC25A overexpression in human cancers might contribute to tumorigenesis.
When exposed to ionizing radiation, eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the ionizing radiation-induced S-phase checkpoint cause 'radioresistant DNA synthesis,' a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia. The CDC25A phosphatase activates CDK2, needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Falck et al. (2001) reported a functional link between ATM (607585), checkpoint signaling kinase CHK2 (604373), and CDC25A, and implicated this mechanism in controlling the S-phase checkpoint. Falck et al. (2001) showed that ionizing radiation-induced destruction of CDC25A requires both ATM and the CHK2-mediated phosphorylation of CDC25A on serine-123. An ionizing radiation-induced loss of CDC25A protein prevents dephosphorylation of CDK2 and leads to a transient blockade of DNA replication. Falck et al. (2001) also showed that tumor-associated CHK2 alleles cannot bind or phosphorylate CDC25A, and that cells expressing these CHK2 alleles, elevated CDC25A, or a CDK2 mutant unable to undergo inhibitory phosphorylation (CDK2AF) fail to inhibit DNA synthesis when irradiated. Falck et al. (2001) concluded that their results support CHK2 as a candidate tumor suppressor, and identify the ATM--CHK2--CDC25A--CDK2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.
Falck et al. (2002) demonstrated that experimental blockade of either the NBS1 (602667)-MRE11 (600814) function or the CHK2-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A-CDK2 pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM. In addition, CDK2-dependent loading of CDC45 (603465) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication.
In Drosophila, expression of the cdc25 phosphatase 'twine,' which promotes progression through meiosis, is regulated by 'Boule' (see 606165), which encodes a key factor of meiosis in male germ cells. Luetjens et al. (2004) investigated whether a common mechanism underlies the block of germ cell maturation observed in idiopathic and nonidiopathic azoospermic patients with meiotic arrest (270960). They examined, by immunohistochemistry, expression of BOULE and CDC25A phosphatase, the human homolog of twine, in 47 men with meiotic arrest, mixed atrophy, or normal spermatogenesis. BOULE protein expression in men with complete spermatogenesis was restricted to stages from leptotene up to stages of late spermatocytes, whereas CDC25A expression ranged from leptotene spermatocytes to elongating spermatids. Although spermatocytes were present in all testicular biopsies with meiotic arrest (28 testes), BOULE protein expression was completely lacking. In addition, in nearly all biopsies in which BOULE was absent, CDC25A was concomitantly lacking. However, no mutations or polymorphisms in the BOULE gene were identified that could explain the lack of BOULE or CDC25A expression. The authors concluded that a major group of infertile men with meiotic arrest lack BOULE protein and its putative target, CDC25A expression. They also concluded that spermatogenic failure seems to arise from factor(s) upstream of BOULE, which are possibly involved in regulating transcription and/or translation of BOULE.
Uto et al. (2004) found Xenopus Chk1, but not Chk2, phosphorylated Xenopus Cdc25a at thr504 and inhibited it from interacting with various Cdk-cyclin complexes through its C terminus. This inhibition, not Cdc25a degradation, was essential for Chk1-induced cell cycle arrest and DNA replication checkpoint in early embryos. C-terminal sites equivalent to thr504 exist in all known Cdc25 family members from yeast to human, and their phosphorylation by Chk1 inhibited all examined Cdc25 family members from interacting with their Cdk-cyclin substrates.
Madlener et al. (2009) showed that moderate heat shock of 42 degrees C caused rapid CDC25A protein degradation and a reduction of cell cycle progression. CDC25A degradation depended on Ser75-CDC25A phosphorylation by p38-MAPK (MAPK14; 600289) and on Ser177-CDC25A phosphorylation by CHK2, which forms a binding site for 14-3-3 (see 113508). Upon heat shock, CDC25A rapidly colocalized with 14-3-3 in the perinuclear space that was accompanied with a decrease of nuclear CDC25A protein levels. Consistently, a 14-3-3 binding-deficient CDC25A double-mutant that cannot be phosphorylated at Ser177 and Tyr506 was not degraded in response to heat shock, and there was no evidence for an increased colocalization of CDC25A with 14-3-3 in the cytosol. Therefore, upon heat shock, p38-MAPK, CHK2, and 14-3-3 were antagonists of CDC25A stability. However, CDC25A was protected by Hsp90AA1 (140571) in HEK293 cells, because the specific inhibition of HSP90 with geldanamycin caused CDC25A degradation in HEK293 cells, implicating that CDC25A is an HSP90 client protein. Specific inhibition of HSP90, together with heat shock, caused and accelerated degradation of CDC25A and was highly cytotoxic. Madlener et al. (2009) concluded that CDC25A is degraded by moderate heat shock and protected by HSP90.
CDC25 phosphatases activate the cell division kinases throughout the cell cycle. Fauman et al. (1998) determined the 2.3-angstrom structure of the human CDC25A catalytic domain. The crystal structure revealed a small alpha/beta domain with a fold unlike previously described phosphatase structures but identical to rhodanese, a sulfur-transfer protein. Only the active-site loop, containing the cys-(X)-5-arg motif, showed similarity to the tyrosine phosphatases. In some crystals, the catalytic cys430 formed a disulfide bond with the invariant cys384, suggesting that CDC25 may be self-inhibited during oxidative stress. Asp383, previously proposed to be the general acid, instead serves a structural role, forming a conserved buried salt bridge. Fauman et al. (1998) proposed that glu431 may act as a general acid.
Demetrick and Beach (1993) mapped the CDC25A gene to 3p21 by fluorescence in situ hybridization with confirmation by PCR analysis of hamster/human somatic cell hybrid DNAs. An area near 3p21 is frequently involved in karyotypic abnormalities in renal carcinomas, small cell carcinomas of the lung, and benign tumors of the salivary gland.
Boutros, R., Lobjois, V., Ducommun, B. CDC25 phosphatases in cancer cells: key players? good targets? Nature Rev. Cancer 7: 495-507, 2007. [PubMed: 17568790] [Full Text: https://doi.org/10.1038/nrc2169]
Demetrick, D. J., Beach, D. H. Chromosome mapping of human CDC25A and CDC25B phosphatases. Genomics 18: 144-147, 1993. [PubMed: 8276402] [Full Text: https://doi.org/10.1006/geno.1993.1440]
Falck, J., Mailand, N., Syljuasen, R. G., Bartek, J., Lukas, J. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410: 842-847, 2001. [PubMed: 11298456] [Full Text: https://doi.org/10.1038/35071124]
Falck, J., Petrini, J. H. J., Williams, B. R., Lukas, J., Bartek, J. The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nature Genet. 30: 290-294, 2002. [PubMed: 11850621] [Full Text: https://doi.org/10.1038/ng845]
Fauman, E. B., Cogswell, J. P., Lovejoy, B., Rocque, W. J., Holmes, W., Montana, V. G., Piwnica-Worms, H., Rink, M. J., Saper, M. A. Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A. Cell 93: 617-625, 1998. [PubMed: 9604936] [Full Text: https://doi.org/10.1016/s0092-8674(00)81190-3]
Galaktionov, K., Beach, D. Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins. Cell 67: 1181-1194, 1991. [PubMed: 1836978] [Full Text: https://doi.org/10.1016/0092-8674(91)90294-9]
Galaktionov, K., Lee, A. K., Eckstein, J., Draetta, G., Meckler, J., Loda, M., Beach, D. CDC25 phosphatases as potential human oncogenes. Science 269: 1575-1577, 1995. [PubMed: 7667636] [Full Text: https://doi.org/10.1126/science.7667636]
Luetjens, C. M., Xu, E. Y., Rejo Pera, R. A., Kamischke, A., Nieschlag, E., Gromoll, J. Association of meiotic arrest with lack of BOULE protein expression in infertile men. J. Clin. Endocr. Metab. 89: 1926-1933, 2004. [PubMed: 15070965] [Full Text: https://doi.org/10.1210/jc.2003-031178]
Madlener, S., Rosner, M., Krieger, S., Giessrigl, B., Gridling, M., Vo, T. P. N., Leisser, C., Lackner, A., Raab, I., Grusch, M., Hengstschlager, M., Dolznig, H., Krupitza, G. Short 42 degrees C heat shock induces phosphorylation and degradation of Cdc25A which depends on p38MAPK, Chk2 and 14.3.3. Hum. Molec. Genet. 18: 1990-2000, 2009. [PubMed: 19289404] [Full Text: https://doi.org/10.1093/hmg/ddp123]
Mailand, N., Falck, J., Lukas, C., Syljuasen, R. G., Welcker, M., Bartek, J., Lukas, J. Rapid destruction of human Cdc25A in response to DNA damage. Science 288: 1425-1429, 2000. [PubMed: 10827953] [Full Text: https://doi.org/10.1126/science.288.5470.1425]
Uto, K., Inoue, D., Shimuta, K., Nakajo, N., Sagata, N. Chk1, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanism. EMBO J. 23: 3386-3396, 2004. [PubMed: 15272308] [Full Text: https://doi.org/10.1038/sj.emboj.7600328]