Synonyms and Variants
G2/Mitotic-specific cyclin B
protein: G2/mitotic-specific cyclin-B1
locus: Chr. 5 q12
protein: G2/mitotic-specific cyclin-B2
locus: Chr. 15 q21.3
protein: G2/mitotic-specific cyclin-B3
locus: Chr. X p11
Mitotic cyclins were discovered in early 1980s by Tim Hunt while he was working in Marine Biological Laboratory in Woods Hole (Mass.) on the cell cycle regulation in sea urchin embryos. Hunt observed at least two protein bands labeled with 35S-methionine appearing cyclically in consonance with the cell cycle (Evans et al. 1983). These two protein bands (which could contain more than two proteins; at that time identification of proteins by available today proteomic methodology did not exist) accumulated during S-phase and disappeared during mitotic division. Especially the band migrating at 56 kD clearly cycled in a periodic manner in synchrony with the cell cycle progression. Therefore, they called this protein cyclin. The unusual behavior of cyclin greatly resembled the cell cycle-dependent appearance and disappearance of the M-phase promoting factor (MPF) – an activity known to induce M-phase, but unidentified at the molecular level at that time (Masui and Markert 1971). The proteins identified by Tim Hunt remained a mystery for almost a decade. In 1989 Jim Maller, Paul Nurse, and their collaborators identified (independently from Tim Hunt’s cyclin) the protein product of the yeast gene cdc2 (p34cdc2) as a component of MPF in frog Xenopus laevis eggs (Gautier et al. 1988). They also showed that this protein has homologues in human and all other Eukaryotes. The p34cdc2 was a protein kinase able to phosphorylate other proteins on serine and threonine residues. They reasoned that if p34cdc2 was identical with MPF it should induce M-phase entry while injected to prophase-arrested oocytes. It did not. Biochemical purification of MPF from Xenopus laevis eggs has shown that it was composed of two proteins: p34cdc2and other, 45–52 KD (depending on the gel used for protein electrophoresis) molecular weight protein. This second component of MPF, always associated with p34cdc2when the kinase was active, was identified as cyclin B, one of the two protein bands initially discovered by Tim Hunt (Gautier et al. 1990). The other band was another mitotic cyclin – cyclin A. The enzyme composed of p34cdc2 and cyclin B, was recognized for long time as MPF on its functional basis, and was named cyclin-dependent kinase 1 (CDK1) on the basis of its biochemical composition. CDK1 was the first member of a family of cyclin-dependent kinases (CDKs), which now counts 20 members (Gopinathan et al. 2011). The importance of discovery of cyclin B and detailed analysis of its role in cell cycle regulation alongside p34cdc2 was recognized by the Nobel Prize in Medicine or Physiology awarded to Tim Hunt (together with Paul Nurse and Leland H. Harwell) in 2001. Recent studies by Takeo Kishimoto have shown that the functional MPF requires, besides p34cdc2 and cyclin B, a third, independent component called the Greatwall kinase (Gwl) (Hara et al. 2012). Gwl allows efficient accumulation of CDK1 substrates by inhibition of PP2A phosphatase.
The stability of cyclin B changes dramatically upon metaphase-anaphase transition. Cyclin B becomes ubiquitinated by APC/C (anaphase promoting complex/cyclosome) ubiquitin ligase, and the whole complex p34cdc2-cyclin B is addressed to the proteasome, which first separates cyclin B from p34cdc2 and then degrades it to peptides and amino acids (Fig. 1, lower part: Mitotic exit) (Nishiyama et al. 2000). While CDK1 loses its regulatory subunit, the active site of the enzyme becomes inaccessible to carry the further phosphorylation reactions and in consequence it becomes inactivated. It was shown experimentally that the separation of cyclin B from p34cdc2 and not its physical degradation inactivates CDK1 upon M-phase exit (Chesnel et al. 2007a). Accordingly, the dynamics of CDK1 inactivation and cyclin B degradation are not strictly parallel; CDK1 activity disappears slightly before total degradation of cyclin B (Fig. 2, rightmost part) (Chesnel et al. 2007b). As cyclin B is constantly synthesized, even during the window of its degradation via APC/C-dependent ubiquitination, the newly synthesized cyclin B participates in the asynchrony of CDK1 inactivation and total cyclin B degradation (ibid.). However, in physiological conditions, proteolytic degradation of cyclin B has a key importance for cell cycle progression because it prevents reactivation of CDK1, since cyclin B must be resynthesized and re-accumulated to the threshold level before new round of CDK1 activation and the triggering of the next M-phase entry. This particular metabolism of cyclin B allowing its stability during the interphase and the rapid and irreversible degradation upon M-phase entry assures the periodicity of the cell cycle from one mitotic division to the next.
Oocyte Maturation and Embryo Development
Cancer, by definition, results from a local hyper proliferation of cells, which during the successive divisions accumulate mutations that further dysregulate the cell cycle. Eventually, they also change phenotype, acquire motility and some stem cell traits, such as immortality and the re-differentiation potential. Faulty regulation of cyclin B can direct cells onto the path of primary hyperplasia, but also participates in further progression of more advanced cancerous stages. High level of cyclin B is a bad prognosis factor in lung cancer, tongue squamous cell carcinoma, and presumably many other cancers (Hassan et al. 2001). Downregulation of CDK1 inhibitor CDC6, observed in some prostate cancers, may result in increased proliferation and participates in cancer progression (El Dika et al. 2014). Of interest there is also the negative correlation between cyclin B and the major tumor suppressor gene p53 product in many cancers (Nigam et al. 2009). p53 inhibits CDK1 activation through inducing p21/WAF1 expression. p21/WAF1 directly binds CDK1 and provokes its nuclear retention (Charrier-Savournin et al. 2004). Also the diminution of cyclin B levels in cancer cells increases p53 expression (if p53-coding gene is not delated), which attenuates cell proliferation and may restore p53 tumor suppressor activity (Kreis et al. 2010). Thus, cyclins B play an important role in cancers and is important potential target for anticancer therapies.
Cyclins B play pivotal role in cell cycle progression and cell division acting as regulatory subunits of p34cdc2. The unprecedented faculty of these proteins to pass from the stable state in interphase to unstable upon mitotic exit allows this major role. Precisely tuned cyclin B oscillations are necessary for female gametes formation, fecundity, and embryo development. Dysregulation of cyclins (e. g., overexpression or not precisely tuned kinase partner activity) promotes cancer formation.