HGNC Approved Gene Symbol: CDC25B
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:3,786,951-3,806,115 (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 (116947), CDC25B, and CDC25C (157680). CDC25B and CDC25C are required primarily for entry into mitosis. CDC25B is proposed to be responsible for the initial activation of CDK1 (116940)-cyclin B (123836) at the centrosome during the G2-M transition, which is then followed by a complete activation of CDK1-cyclin B complexes by CDC25C in the nucleus at the onset of mitosis (summary by Boutros et al., 2007).
Lane et al. (1993) demonstrated by fluorescence in situ hybridization that CDC25B maps to 20p13. PCR analysis of a monochromosomal hybrid cell panel yielded results supporting this chromosome assignment. Demetrick and Beach (1993) also mapped CDC25B to chromosome 20p13 by fluorescence in situ hybridization with confirmation by the polymerase chain reaction of hamster/human somatic cell hybrid DNA.
Bulavin et al. (2001) reported that p38 kinase (600289) has a critical role in the initiation of a G2 delay after ultraviolet radiation. Inhibition of p38 blocks the rapid initiation of this checkpoint in both human and murine cells after ultraviolet radiation. In vitro, p38 binds and phosphorylates CDC25B at serines 309 and 361, and CDC25C at serine-216; phosphorylation of these residues is required for binding to 14-3-3 proteins (see 113508). In vivo, inhibition of p38 prevents both phosphorylation of CDC25B at serine-309 and 14-3-3 binding after ultraviolet radiation, and mutation of this site is sufficient to inhibit the checkpoint initiation. In contrast, in vivo CDC25C binding to 14-3-3 is not affected by p38 inhibition after ultraviolet radiation. Bulavin et al. (2001) proposed that regulation of CDC25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation.
By mutation and deletion analyses, Dalvai et al. (2011) showed that downregulation of human CDC25B by p53 (TP53; 191170) was dependent on the presence of functional SP1 (189906)/SP3 (601804)- and NFY (see 605344)-binding sites in CDC25B. Chromatin immunoprecipitation analysis showed that p53 bound to the CDC25B promoter and mediated transcriptional attenuation through SP1 and NFY transcription factors. Dalvai et al. (2011) concluded that CDC25B is downregulated by the basal level of p53 and proposed that CDC25B upregulation after p53 loss may contribute to tumorigenesis.
Lincoln et al. (2002) generated Cdc25b-deficient mice by targeted disruption and found that they were viable. As compared with wildtype cells, fibroblasts from Cdc25b -/- mice grew vigorously in culture and arrested normally in response to DNA damage. Female Cdc25b -/- mice were sterile and Cdc25b -/- oocytes remained arrested at prophase with low maturation-promoting factor activity. Microinjection of wildtype Cdc25b mRNA into Cdc25b -/- oocytes caused activation of maturation-promoting factor and resumption of meiosis. Thus, Lincoln et al. (2002) concluded that Cdc25b -/- female mice were sterile because of permanent meiotic arrest resulting from the inability to activate the maturation-promoting factor component CDK1. Cdc25b is therefore essential for meiotic resumption in female mice. Lincoln et al. (2002) stated that mice lacking Cdc25b provided the first genetic model for studying the mechanisms regulating prophase arrest in vertebrates.
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]
Bulavin, D. V., Higashimoto, Y., Popoff, I. J., Gaarde, W. A., Basrur, V., Potapova, O., Appella, E., Fornace, A. J., Jr. Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 411: 102-107, 2001. [PubMed: 11333986] [Full Text: https://doi.org/10.1038/35075107]
Dalvai, M., Mondesert, O., Bourdon, J.-C., Ducommun, B., Dozier, C. Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors. Oncogene 30: 2282-2288, 2011. [PubMed: 21242964] [Full Text: https://doi.org/10.1038/onc.2010.588]
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]
Lane, S. A., Baker, E., Sutherland, G. R., Tonks, I., Hayward, N., Ellem, K. The human cell cycle gene CDC25B is located at 20p13. Genomics 15: 693-694, 1993. [PubMed: 8468065] [Full Text: https://doi.org/10.1006/geno.1993.1129]
Lincoln, A. J., Wickramasinghe, D., Stein, P., Schultz, R. M., Palko, M. E., De Miguel, M. P., Tessarollo, L., Donovan, P. J. Cdc25b phosphatase is required for resumption of meiosis during oocyte maturation. Nature Genet. 30: 446-449, 2002. [PubMed: 11912493] [Full Text: https://doi.org/10.1038/ng856]