Alternative titles; symbols
HGNC Approved Gene Symbol: CCNB1
Cytogenetic location: 5q13.2 Genomic coordinates (GRCh38): 5:69,167,150-69,178,245 (from NCBI)
By cloning cDNA from HeLa cells, Pines and Hunter (1989) obtained a HeLa cDNA encoding CCNB1. The deduced 433-amino acid protein has a central conserved cyclin box region. CCNB1 was expressed predominantly in the G2/M phase of cell division.
By genetic mapping in the mouse using human cyclin B1 probes, Lock et al. (1992) identified 10 cyclin B1-related sequences located on chromosomes 4, 5, 7, 8, 13, 14, 15, and 17. In Northern analysis, 3 cyclin B1-related transcripts of 1.7, 2.1, and 2.7 kb were detected in embryonic stem cells and postimplantation embryos from day 9.5 to 15.5 of development. The multiple cyclin B1-related sequences in the mouse genome and the multiple cyclin B1 mRNAs raised the possibility that the seemingly redundant cyclin B genes may have developmental- and/or cell-type-specific functions.
Pines and Hunter (1989) reported that CCNB1 complexes with p34(cdc2) (CDK1; 116940) to form mitosis-promoting factor (also known as maturation-promoting factor, or M phase-promoting factor), or MPF.
In vertebrate cells, the nuclear entry of MPF during prophase is thought to be essential for the induction and coordination of M-phase events. Phosphorylation of cyclin B1 is central to its nuclear translocation. Toyoshima-Morimoto et al. (2001) purified a protein kinase from Xenopus M-phase extracts that phosphorylates a crucial serine residue (S147) in the middle of the nuclear export signal sequence of cyclin B1. They identified this kinase as Plx1, a Xenopus homolog of PLK1 (602098). During cell cycle progression in HeLa cells, a change in the kinase activity of endogenous PLK1 toward S147 and/or S133 correlated with a kinase activity in the cell extracts. An anti-PLK1 antibody depleted the M-phase extracts of the kinase activity toward S147 and/or S133. An antiphospho-S147 antibody reacted specifically with cyclin B1 only during G2/M phase. A mutant cyclin B1 in which S133 and S147 were replaced by alanines remained in the cytoplasm, whereas wildtype cyclin B1 accumulated in the nucleus during prophase. Coexpression of constitutively active PLK1 stimulated nuclear entry of cyclin B1. Toyoshima-Morimoto et al. (2001) concluded that PLK1 may be involved in targeting MPF to the nucleus during prophase.
Tsukahara et al. (2010) isolated a fission yeast cyclin B mutant defective specifically in chromosome biorientation. Accordingly, Tsukahara et al. (2010) identified Cdk1 (116940)-cyclin B-dependent phosphorylation of survivin (603352). Preventing survivin phosphorylation impaired centromere chromosomal passenger complex (CPC) targeting as well as chromosome biorientation, whereas phosphomimetic survivin suppressed the biorientation defect in the cyclin B mutant. Survivin phosphorylation promoted direct binding with shugoshin (see 609168), which Tsukahara et al. (2010) defined as a conserved centromeric adaptor of the CPC. In human cells, the phosphorylation of borealin (609977) has a comparable role. Tsukahara et al. (2010) concluded that this study resolved the conserved mechanisms of CPC targeting to centromeres, highlighting a key role of Cdk1-cyclin B in chromosome biorientation.
Cyclin A2 (CCNA2; 123835) is first detected during S phase, then shuttles dynamically between the cytoplasm and nucleus, and is finally degraded during prometaphase. Using RNA interference and time-lapse fluorescence microscopy with synchronized HeLa cells, Gong and Ferrell (2010) found that cyclin A2 was required for activation and nuclear accumulation of cyclin B1-CDK1, as well as timely breakdown of the nuclear envelope, histone H3 phosphorylation, and chromatin condensation. Expression of constitutively nuclear cyclin B1 abrogated many of these effects, and chromatin condensation coincided with translocation of cyclin B1 to the nucleus. In contrast with knockdown of cyclin A2, knockdown of cyclin B1, or, more potently, of both cyclins B1 and B2 (CCNB2; 602755), had more dramatic effects on later mitotic events and resulted in loss of mitotic arrest in the presence of microtubule depolymerization. Gong and Ferrell (2010) hypothesized that cyclin A2 helps initiate mitosis, in part, by activating cyclin B1-CDK1 activation and nuclear translocation.
Nam and van Deursen (2014) found that mouse embryonic fibroblasts (MEFs) or splenocytes overexpressing transgenic wildtype Ccnb1 or Ccnb2 were prone to aneuploidy. However, the underlying causes of aneuploidy were distinct, with Ccnb1 overexpression inducing chromatin bridges or anaphase failure, and Ccnb2 overexpression causing lagging chromosomes. In Ccnb1-overexpressing cells, the severity of mitotic phenotypes correlated inversely with separase (ESPL1; 604143) activity. Timing of S/G2, prophase, prometaphase, and metaphase appeared normal in Ccnb1-overexpressing MEFs.
Milatovich and Francke (1992) mapped the CCNB1 gene to 5q13-qter by Southern blot analysis of human/Chinese hamster somatic cell hybrid panels. Based on this information and known evolutionary conservation of chromosomal regions, they proposed that the homologous cyclin B1 locus, Cycb-4, on mouse chromosome 13 is a functional gene. Using cDNA isolated by Pines and Hunter (1989) for fluorescence in situ hybridization, Sartor et al. (1992) mapped the CCNB1 gene to 5q12.
Two B-type cyclins, B1 and B2 (602755), have been identified in mammals. Proliferating cells express both cyclins, which bind to and activate p34 (CDC2). To test whether the 2 B-type cyclins have distinct roles, Brandeis et al. (1998) generated lines of transgenic mice, one lacking cyclin B1 and the other lacking B2. Cyclin B1 proved to be an essential gene; no homozygous B1-null pups were born. In contrast, nullizygous B2 mice developed normally and did not display any obvious abnormalities. Both male and female cyclin B2-null mice were fertile, which was unexpected in view of the high levels and distinct patterns of expression of cyclin B2 during spermatogenesis. Brandeis et al. (1998) showed that the expression of cyclin B1 overlaps the expression of cyclin B2 in the mature testis, but not vice versa. Cyclin B1 can be found both on intracellular membranes and free in the cytoplasm, in contrast to cyclin B2, which is membrane-associated. These observations suggested that cyclin B1 may compensate for the loss of cyclin B2 in the mutant mice, and implies that cyclin B1 is capable of targeting the p34(CDC2) kinase to the essential substrates of cyclin B2.
In higher eukaryotes, the S phase and M phase of the cell cycle are triggered by different cyclin-dependent kinases (CDKs). For example, in frog egg extracts, Cdk1 (116940)-cyclin B catalyzes entry into mitosis but cannot trigger DNA replication. Two hypotheses can explain this observation: either Cdk1-cyclin B fails to recognize the key substrates of its S-phase-promoting counterparts, or its activity is somehow regulated to prevent it from activating DNA synthesis. Moore et al. (2003) demonstrated that Cdk1-cyclin B1 has cryptic S-phase-promoting abilities that can be unmasked by relocating it from the cytoplasm to the nucleus and moderately stimulating its activity with Cdc25 phosphatase (157680). Subcellular localization of vertebrate CDKs and the control of their activity are thus critical factors for determining their specificity.
Matsuo et al. (2003) studied the regenerating liver of mice and demonstrated that the circadian clock controls expression of cell cycle-related genes that in turn modulate the expression of active cyclin B1-Cdc2 (116940) kinase, a key regulator of mitosis. Among these genes, Matsuo et al. (2003) found that expression of Wee1 (193525) was directly regulated by the molecular components of the circadian clockwork. In contrast, the circadian clockwork oscillated independently of the cell cycle in single cells. Matsuo et al. (2003) concluded that the intracellular circadian clockwork can control the cell division cycle directly and unidirectionally in proliferating cells.
Brandeis, M., Rosewell, I., Carrington, M., Crompton, T., Jacobs, M. A., Kirk, J., Gannon, J., Hunt, T. Cyclin B2-null mice develop normally and are fertile whereas cyclin B1-null mice die in utero. Proc. Nat. Acad. Sci. 95: 4344-4349, 1998. [PubMed: 9539739] [Full Text: https://doi.org/10.1073/pnas.95.8.4344]
Gong, D., Ferrell, J. E., Jr. The roles of cyclin A2, B1, and B2 in early and late mitotic events. Molec. Biol. Cell 21: 3149-3161, 2010. [PubMed: 20660152] [Full Text: https://doi.org/10.1091/mbc.E10-05-0393]
Lock, L. F., Pines, J., Hunter, T., Gilbert, D. J., Gopalan, G., Jenkins, N. A., Copeland, N. G., Donovan, P. J. A single cyclin A gene and multiple cyclin B1-related sequences are dispersed in the mouse genome. Genomics 13: 415-424, 1992. [PubMed: 1535334] [Full Text: https://doi.org/10.1016/0888-7543(92)90262-q]
Matsuo, T., Yamaguchi, S., Mitsui, S., Emi, A., Shimoda, F., Okamura, H. Control mechanism of the circadian clock for timing of cell division in vivo. Science 302: 255-259, 2003. [PubMed: 12934012] [Full Text: https://doi.org/10.1126/science.1086271]
Milatovich, A., Francke, U. Human cyclin B1 gene (CCNB1) assigned to chromosome 5 (q13-qter). Somat. Cell Molec. Genet. 18: 303-307, 1992. [PubMed: 1386686] [Full Text: https://doi.org/10.1007/BF01233865]
Moore, J. D., Kirk, J. A., Hunt, T. Unmasking the S-phase-promoting potential of cyclin B1. Science 300: 987-990, 2003. [PubMed: 12738867] [Full Text: https://doi.org/10.1126/science.1081418]
Nam, H.-J., van Deursen, J. M. Cyclin B2 and p53 control proper timing of centrosome separation. Nature Cell Biol. 16: 535-546, 2014.
Pines, J., Hunter, T. Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34(cdc2). Cell 58: 833-846, 1989. [PubMed: 2570636] [Full Text: https://doi.org/10.1016/0092-8674(89)90936-7]
Sartor, H., Ehlert, F., Grzeschik, K.-H., Muller, R., Adolph, S. Assignment of two human cell cycle genes, CDC25C and CCNB1, to 5q31 and 5q12, respectively. Genomics 13: 911-912, 1992. [PubMed: 1386342] [Full Text: https://doi.org/10.1016/0888-7543(92)90190-4]
Toyoshima-Morimoto, F., Taniguchi, E., Shinya, N., Iwamatsu, A., Nishida, E. Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature 410: 215-220, 2001. Note: Erratum: Nature 410: 847 only, 2001. [PubMed: 11242082] [Full Text: https://doi.org/10.1038/35065617]
Tsukahara, T., Tanno, Y., Watanabe, Y. Phosphorylation of the CPC by Cdk1 promotes chromosome bi-orientation. Nature 467: 719-723, 2010. [PubMed: 20739936] [Full Text: https://doi.org/10.1038/nature09390]