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Medicine May 2017Cyclin B plays a crucial role in cancer cell cycle progression and is overexpressed in many human cancers, including breast cancer. However, the prognostic value of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cyclin B plays a crucial role in cancer cell cycle progression and is overexpressed in many human cancers, including breast cancer. However, the prognostic value of cyclin B expression in breast cancer is controversial. We performed a meta-analysis to assess the clinicopathological and prognostic significance of cyclin B expression in breast cancer.
METHODS
We searched PubMed, web of science, and Embase databases to retrieve the publications investigating the association between cyclin B expression and clinicopathological/prognostic significance in breast cancer patients. The pooled hazard ratio (HR) or odds ratio (OR) with its 95% confidence intervals (CIs) were used to estimate the effects.
RESULTS
Ten studies with 2366 breast cancer patients were included to evaluate the association between cyclin B expression and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and clinicopathological parameters. The results showed that cyclin B overexpression in breast cancer patients was significantly associated with both poor OS (univariate analysis: HR = 2.38, 95% CI = 1.72-3.30, P < .001), DFS (univariate analysis: HR = 1.86, 95% CI = 1.50-2.32, P < .001; multivariate analysis: HR = 1.75, 95% CI = 1.22-2.52, P = .003), and DSS (multivariate analysis: HR = 5.42, 95% CI = 2.15-13.66, P < .001). Additionally, cyclin B overexpression was significantly associated with lymphatic invasion (OR = 2.58, 95% CI = 1.03-6.46, P = .017).
CONCLUSION
Cyclin B overexpression appears to be an independent potential prognostic marker to DSS and DFS for breast cancer. Further studies with large sample size are needed to dissect the relationship between cyclin B and clinicopathological features or prognosis of breast cancer.
Topics: Biomarkers, Tumor; Breast Neoplasms; Cyclin B; Humans; Prognosis
PubMed: 28489780
DOI: 10.1097/MD.0000000000006860 -
Molecular Biology of the Cell Oct 2020Ubiquitin-dependent proteolysis of cyclin B and securin initiates sister chromatid segregation and anaphase. The anaphase-promoting complex/cyclosome and its coactivator...
Ubiquitin-dependent proteolysis of cyclin B and securin initiates sister chromatid segregation and anaphase. The anaphase-promoting complex/cyclosome and its coactivator CDC20 (APC/C) form the main ubiquitin E3 ligase for these two proteins. APC/C is regulated by CDK1-cyclin B and counteracting PP1 and PP2A family phosphatases through modulation of both activating and inhibitory phosphorylation. Here, we report that PP1 promotes cyclin B destruction at the onset of anaphase by removing specific inhibitory phosphorylation in the N-terminus of CDC20. Depletion or chemical inhibition of PP1 stabilizes cyclin B and results in a pronounced delay at the metaphase-to-anaphase transition after chromosome alignment. This requirement for PP1 is lost in cells expressing CDK1 phosphorylation-defective CDC20 mutants. These CDC20 cells show a normal spindle checkpoint response and rapidly destroy cyclin B once all chromosomes have aligned and enter into anaphase in the absence of PP1 activity. PP1 therefore facilitates the metaphase-to-anaphase transition by promoting APC/C-dependent destruction of cyclin B in human cells.
Topics: Anaphase; Cdc20 Proteins; Chromosome Segregation; Cyclin B; HeLa Cells; Humans; Metaphase; Phosphorylation; Protein Processing, Post-Translational; Proteolysis; Receptors, Neuropeptide Y
PubMed: 32755477
DOI: 10.1091/mbc.E20-04-0252 -
PLoS Genetics Aug 2022In yeast and animals, cyclin B binds and activates the cyclin-dependent kinase ('CDK') CDK1 to drive entry into mitosis. We show that CYCB1, the sole cyclin B in...
In yeast and animals, cyclin B binds and activates the cyclin-dependent kinase ('CDK') CDK1 to drive entry into mitosis. We show that CYCB1, the sole cyclin B in Chlamydomonas, activates the plant-specific CDKB1 rather than the CDK1 ortholog CDKA1, confirming and extending previous results. Time-lapse microscopy shows that CYCB1 is synthesized before each division in the multiple fission cycle, then is rapidly degraded 3-5 minutes before division occurs. CYCB1 degradation is dependent on the anaphase-promoting complex (APC). Like CYCB1, CDKB1 is not synthesized until late G1; however, CDKB1 is not degraded with each division within the multiple fission cycle, but is degraded after all divisions have ceased. The microtubule plus-end-binding protein EB1 labeled with mNeonGreen allowed detection of mitotic events in live cells. The earliest detectable step in mitosis, splitting of polar EB1 signal into two foci, likely associated with future spindle poles, was dependent on CYCB1. CYCB1-GFP localized close to these foci immediately before spindle formation. Spindle breakdown, cleavage furrow formation and accumulation of EB1 in the furrow were dependent on the APC. In interphase, rapidly growing microtubules are marked by 'comets' of EB1; comets are absent in the absence of APC function. Thus CYCB1/CDKB1 and the APC modulate microtubule function and assembly while regulating mitotic progression. Genetic results suggest an independent additional role for the APC in regulating sister chromatid cohesion; this role is likely conserved across eukaryotes.
Topics: Anaphase; Anaphase-Promoting Complex-Cyclosome; Animals; Cell Cycle Proteins; Chlamydomonas; Cyclin B; Cyclin-Dependent Kinases; Mitosis; Spindle Apparatus
PubMed: 35981052
DOI: 10.1371/journal.pgen.1009997 -
Chromosoma Dec 2015Maturation or M phase-promoting factor (MPF) is the universal inducer of M phase common to eukaryotic cells. MPF was originally defined as a transferable activity that... (Review)
Review
Maturation or M phase-promoting factor (MPF) is the universal inducer of M phase common to eukaryotic cells. MPF was originally defined as a transferable activity that can induce the G2/M phase transition in recipient cells. Today, however, MPF is assumed to describe an activity that exhibits its effect in donor cells, and furthermore, MPF is consistently equated with the kinase cyclin B-Cdk1. In some conditions, however, MPF, as originally defined, is undetectable even though cyclin B-Cdk1 is fully active. For over three decades, this inconsistency has remained a long-standing puzzle. The enigma is now resolved through the elucidation that MPF, defined as an activity that exhibits its effect in recipient cells, consists of at least two separate kinases, cyclin B-Cdk1 and Greatwall (Gwl). Involvement of Gwl in MPF can be explained by its contribution to the autoregulatory activation of cyclin B-Cdk1 and by its stabilization of phosphorylations on cyclin B-Cdk1 substrates, both of which are essential when MPF induces the G2/M phase transition in recipient cells. To accomplish these tasks, Gwl helps cyclin B-Cdk1 by suppressing protein phosphatase 2A (PP2A)-B55 that counteracts cyclin B-Cdk1. MPF, as originally defined, is thus not synonymous with cyclin B-Cdk1, but is instead a system consisting of both cyclin B-Cdk1 that directs mitotic entry and Gwl that suppresses the anti-cyclin B-Cdk1 phosphatase. The current view that MPF is a synonym for cyclin B-Cdk1 in donor cells is thus imprecise; instead, MPF is best regarded as the entire pathway involved in the autoregulatory activation of cyclin B-Cdk1, with specifics depending on the experimental system.
Topics: Animals; Cyclin B; Eukaryota; G2 Phase Cell Cycle Checkpoints; Humans; Maturation-Promoting Factor; Mitosis
PubMed: 25712366
DOI: 10.1007/s00412-015-0508-y -
Cells Nov 2023The cyclin-dependent kinase 1 (Cdk1)-cyclin B (CycB) complex plays critical roles in cell-cycle regulation. Before male meiosis, CycB is exported from the nucleus to...
The cyclin-dependent kinase 1 (Cdk1)-cyclin B (CycB) complex plays critical roles in cell-cycle regulation. Before male meiosis, CycB is exported from the nucleus to the cytoplasm via the nuclear porin 62kD (Nup62) subcomplex of the nuclear pore complex. When this export is inhibited, Cdk1 is not activated, and meiosis does not initiate. We investigated the mechanism that controls the cellular localization and activation of Cdk1. Cdk1-CycB continuously shuttled into and out of the nucleus before meiosis. Overexpression of CycB, but not that of CycB with nuclear localization signal sequences, rescued reduced cytoplasmic CycB and inhibition of meiosis in -silenced cells. Full-scale Cdk1 activation occurred in the nucleus shortly after its rapid nuclear entry. Cdk1-dependent centrosome separation did not occur in silenced cells, whereas Cdk1 interacted with Cdk-activating kinase and Twine/Cdc25C in the nuclei of silenced cells, suggesting the involvement of another suppression mechanism. Silencing of rescued Cdk1 inhibition and initiated meiosis. Nuclear export of Cdk1 ensured its escape from inhibition by a cyclin-dependent kinase inhibitor. The complex re-entered the nucleus via importin β at the onset of meiosis. We propose a model regarding the dynamics and activation mechanism of Cdk1-CycB to initiate male meiosis.
Topics: Animals; Male; Drosophila; Active Transport, Cell Nucleus; Cytoplasm; Drosophila Proteins; Meiosis; Nuclear Pore Complex Proteins; Cyclin B
PubMed: 37998346
DOI: 10.3390/cells12222611 -
The EMBO Journal Jun 2020Two mitotic cyclin types, cyclin A and B, exist in higher eukaryotes, but their specialised functions in mitosis are incompletely understood. Using degron tags for rapid...
Two mitotic cyclin types, cyclin A and B, exist in higher eukaryotes, but their specialised functions in mitosis are incompletely understood. Using degron tags for rapid inducible protein removal, we analyse how acute depletion of these proteins affects mitosis. Loss of cyclin A in G2-phase prevents mitotic entry. Cells lacking cyclin B can enter mitosis and phosphorylate most mitotic proteins, because of parallel PP2A:B55 phosphatase inactivation by Greatwall kinase. The final barrier to mitotic establishment corresponds to nuclear envelope breakdown, which requires a decisive shift in the balance of cyclin-dependent kinase Cdk1 and PP2A:B55 activity. Beyond this point, cyclin B/Cdk1 is essential for phosphorylation of a distinct subset of mitotic Cdk1 substrates that are essential to complete cell division. Our results identify how cyclin A, cyclin B and Greatwall kinase coordinate mitotic progression by increasing levels of Cdk1-dependent substrate phosphorylation.
Topics: CDC2 Protein Kinase; Cell Line; Cyclin A; Cyclin B; Humans; Mitosis; Protein Phosphatase 2
PubMed: 32350921
DOI: 10.15252/embj.2020104419 -
Philosophical Transactions of the Royal... Sep 1999The degradation of the cyclin B subunit of protein kinase Cdk1/cyclin B is required for inactivation of the kinase and exit from mitosis. Cyclin B is degraded by the... (Review)
Review
The degradation of the cyclin B subunit of protein kinase Cdk1/cyclin B is required for inactivation of the kinase and exit from mitosis. Cyclin B is degraded by the ubiquitin pathway, a system involved in most selective protein degradation in eukaryotic cells. In this pathway, proteins are targeted for degradation by ligation to ubiquitin, a process carried out by the sequential action of three enzymes: the ubiquitin-activating enzyme E1, a ubiquitin-carrier protein E2 and a ubiquitin-protein ligase E3. In the system responsible for cyclin B degradation, the E3-like function is carried out by a large complex called cyclosome or anaphase-promoting complex (APC). In the early embryonic cell cycles, the cyclosome is inactive in the interphase, but becomes active at the end of mitosis. Activation requires phosphorylation of the cyclosome/APC by protein kinase Cdk1/cyclin B. The lag kinetics of cyclosome activation may be explained by Suc1-assisted multiple phosphorylations of partly phosphorylated complex. The presence of a Fizzy/Cdc20-like protein is necessary for maximal activity of the mitotic form of cyclosome/APC in cyclin-ubiquitin ligation.
Topics: Anaphase-Promoting Complex-Cyclosome; Animals; Cell Cycle; Cell Cycle Proteins; Cyclin B; Drosophila; Drosophila Proteins; Ligases; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligases; Xenopus
PubMed: 10582242
DOI: 10.1098/rstb.1999.0500 -
Archives of Pathology & Laboratory... Aug 2019Clear cell sarcoma of the kidney is the second most common primary renal malignancy in childhood. It is histologically diverse, making accurate diagnosis challenging in... (Review)
Review
Clear cell sarcoma of the kidney is the second most common primary renal malignancy in childhood. It is histologically diverse, making accurate diagnosis challenging in some cases. Recent molecular studies have uncovered exon 15 internal tandem duplications in most cases, and fusion in a few cases, with the remaining cases having other genetic mutations, including fusion and mutations. Although clear cell sarcoma of the kidney has no specific immunophenotype, several markers including cyclin D1, nerve growth factor receptor, and BCOR (BCL6 corepressor) have emerged as potential diagnostic aides. This review provides a concise account of recent advances in our understanding of clear cell sarcoma of the kidney to serve as a practical update for the practicing pathologist.
Topics: Biomarkers, Tumor; Child; Cyclin B; Diagnosis, Differential; Humans; Kidney; Kidney Neoplasms; Mutation; Proto-Oncogene Proteins; Repressor Proteins; Sarcoma, Clear Cell
PubMed: 30628851
DOI: 10.5858/arpa.2018-0045-RS -
Developmental Cell Oct 2022To ensure successful offspring ploidy, vertebrate oocytes must halt the cell cycle in meiosis II until sperm entry. Emi2 is essential to keep oocytes arrested until...
To ensure successful offspring ploidy, vertebrate oocytes must halt the cell cycle in meiosis II until sperm entry. Emi2 is essential to keep oocytes arrested until fertilization. However, how this arrest is implemented exclusively in meiosis II and not prematurely in meiosis I has until now remained enigmatic. Using mouse and frog oocytes, we show here that cyclin B3, an understudied B-type cyclin, is essential to keep Emi2 levels low in meiosis I. Direct phosphorylation of Emi2 at an evolutionarily highly conserved site by Cdk1/cyclin B3 targets Emi2 for degradation. In contrast, Cdk1/cyclin B1 is inefficient in Emi2 phosphorylation, and this provides a molecular explanation for the requirement of different B-type cyclins for oocyte maturation. Cyclin B3 degradation at exit from meiosis I enables Emi2 accumulation and thus timely arrest in meiosis II. Our findings illuminate the evolutionarily conserved mechanisms that control oocyte arrest for fertilization at the correct cell-cycle stage, which is essential for embryo viability.
Topics: Animals; Cyclin B; Cyclin B1; Cyclins; F-Box Proteins; Fertilization; Male; Meiosis; Mice; Oocytes; Semen; Vertebrates
PubMed: 36182686
DOI: 10.1016/j.devcel.2022.09.005 -
Cell Cycle (Georgetown, Tex.) Oct 2017The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid... (Review)
Review
The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid separation, and cell division. Mathematical models describing the biochemical interaction networks of cell cycle regulators attribute these properties to underlying bistable switches, which inherently generate robust, switch-like, and irreversible transitions between states. We have recently presented new mathematical models for two control systems that regulate crucial transitions in the cell cycle: mitotic entry and exit, and the mitotic checkpoint. Each of the two control systems is characterized by two interlinked bistable switches. In the case of mitotic checkpoint control, these switches are mutually activating, whereas in the case of the mitotic entry/exit network, the switches are mutually inhibiting. In this Perspective we describe the qualitative features of these regulatory motifs and show that having two interlinked bistable mechanisms further enhances robustness and irreversibility. We speculate that these network motifs also underlie other cell cycle transitions and cellular transitions between distinct biochemical states.
Topics: Animals; CDC2 Protein Kinase; Cyclin B; Humans; M Phase Cell Cycle Checkpoints; Mitosis; Models, Biological
PubMed: 28902568
DOI: 10.1080/15384101.2017.1371885