Cyclin B1

G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene.[4]

CCNB1
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 2B9R, 2JGZ, 4Y72, 5HQ0, 4YC3
Identifiers
Aliases	CCNB1, CCNB, cyclin B1
External IDs	OMIM: 123836 MGI: 3648694 HomoloGene: 68982 GeneCards: CCNB1
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q13.2 Start 69,167,135 bp[1] End 69,178,245 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • histone kinase activity • kinase activity • patched binding • GO:0001948 protein binding • cyclin-dependent protein serine/threonine kinase activity • GO:0016534 cyclin-dependent protein serine/threonine kinase activator activity • ubiquitin-like protein ligase binding • protein kinase binding • protein kinase activity • cyclin-dependent protein serine/threonine kinase regulator activity Cellular component • cytoplasm • centrosome • spindle pole • membrane • condensed nuclear chromosome outer kinetochore • nucleoplasm • microtubule organizing center • cytoskeleton • cell nucleus • cytosol • mitochondrial matrix • cyclin B1-CDK1 complex • cyclin-dependent protein kinase holoenzyme complex Biological process • negative regulation of protein phosphorylation • response to DDT • regulation of mitotic cell cycle spindle assembly checkpoint • histone H3-S10 phosphorylation involved in chromosome condensation • positive regulation of mRNA 3'-end processing • tissue regeneration • positive regulation of fibroblast proliferation • cellular response to iron(III) ion • cellular response to organic cyclic compound • response to mechanical stimulus • positive regulation of mitotic cell cycle • in utero embryonic development • negative regulation of gene expression • regulation of cell cycle • cell division • positive regulation of attachment of spindle microtubules to kinetochore • protein phosphorylation • mitotic nuclear envelope disassembly • positive regulation of histone phosphorylation • cellular response to fatty acid • positive regulation of cardiac muscle cell proliferation • positive regulation of cell cycle • G2/M transition of mitotic cell cycle • oocyte maturation • spermatogenesis • cell cycle • mitotic metaphase plate congression • anaphase-promoting complex-dependent catabolic process • regulation of chromosome condensation • digestive tract development • ventricular cardiac muscle cell development • cellular response to hypoxia • response to toxic substance • response to drug • GO:0043148 mitotic spindle organization • GO:0007067 mitotic cell cycle • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest • positive regulation of mitochondrial ATP synthesis coupled electron transport • positive regulation of G2/M transition of mitotic cell cycle • positive regulation of cyclin-dependent protein serine/threonine kinase activity • macromolecular complex assembly • regulation of cyclin-dependent protein serine/threonine kinase activity • regulation of mitotic nuclear division • positive regulation of cell proliferation • transcription initiation from RNA polymerase II promoter • regulation of mitotic cell cycle phase transition Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	891	434175
Ensembl	ENSG00000134057	n/a
UniProt	P14635	n/a
RefSeq (mRNA)	NM_031966 NM_001354844 NM_001354845	n/a
RefSeq (protein)	NP_114172 NP_001341773 NP_001341774	n/a
Location (UCSC)	Chr 5: 69.17 – 69.18 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Function

Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34 (Cdk1) to form the maturation-promoting factor (MPF). Two alternative transcripts have been found, a constitutively expressed transcript and a cell cycle-regulated transcript that is expressed predominantly during G2/M phase of the cell cycle. The different transcripts result from the use of alternate transcription initiation sites.[5]

Cyclin B1 contributes to the switch-like all or none behavior of the cell in deciding to commit to mitosis. Its activation is well-regulated, and positive feedback loops ensure that once the cyclin B1-Cdk1 complex is activated, it is not deactivated. Cyclin B1-Cdk1 is involved in the early events of mitosis, such as chromosome condensation, nuclear envelope breakdown, and spindle pole assembly.

Once activated, cyclin B1-Cdk1 promotes several of the events of early mitosis. The active complex phosphorylates and activates 13S condensin,[6] which helps to condense chromosomes.

Another important function of the cyclin B1-Cdk1 complex is to break down the nuclear envelope. The nuclear envelope is a membranous structure containing large protein complexes supported by a network of nuclear lamins. Phosphorylation of the lamins by cyclin B1-Cdk1 causes them to dissociate,[7] compromising the structural integrity of the nuclear envelope so that it breaks down. The destruction of the nuclear envelope is important because it allows the mitotic spindle to access the chromosomes.

Regulation

Cyclin B1 accumulates throughout the cell cycle but must be activated. It is degraded at the end of mitosis and accumulates again during the next cell cycle.

Like all cyclins, levels of cyclin B1 oscillate over the course of the cell cycle. Just prior to mitosis, a large amount of cyclin B1 is present in the cell, but it is inactive due to phosphorylation of Cdk1 by the Wee1 kinase. The complex is activated by dephosphorylation by the phosphatase Cdc25.[8] Cdc25 is always present in the cell but must be activated by phosphorylation. A possible trigger for activation is phosphorylation by cyclin A-Cdk, which functions before cyclin B1-Cdk in the cell cycle. Active Cdk1 is also capable of phosphorylating and activating Cdc25 and thus promote its own activation, resulting in a positive feedback loop. Once cyclin B1-Cdk1 is activated, it remains stably active for the rest of mitosis.

Another mechanism by which cyclin B1-Cdk1 activity is regulated is through subcellular localization. Before mitosis almost all cyclin B1 in the cell is located in the cytoplasm, but in late prophase it relocates to the nucleus. This is regulated by the phosphorylation of cyclin B1, in contrast to phosphorylation of Cdk1 regulating the activity of the complex. Phosphorylation of cyclin B1 causes it to be imported to the nucleus,[9] and phosphorylation also prevents export from the nucleus by blocking the nuclear export signal.[10] Cyclin B1 is phosphorylated by Polo kinase and Cdk1, again setting up a positive feedback loop that commits cyclin B1-Cdk1 to its fate.

At the end of mitosis, cyclin B1 is targeted for degradation by the APC through its APC localization sequence, permitting the cell to exit mitosis.

Interactions

Cyclin B1 has been shown to interact with Cdk1,[11][12]

[13][14] GADD45A[15][16] and RALBP1.[17]

Cancer

One of the hallmarks of cancer is the lack of regulation in the cell cycle. The role of cyclin B1 is to transition the cell from G2 to M phase but becomes unregulated in cancer cells where overexpression of cyclin B1 can lead to uncontrolled cell growth by binding to its partner Cdks. Binding of Cdks can lead to phosphorylation of other substrates at inappropriate time and unregulated proliferation.[18] This is a consequence of p53, tumor suppressor protein, being inactivated. Wild-type p53 have been shown to suppress cyclin B1 expression.[19][20]

Previous work has shown that high cyclin B1 expression levels are found in variety of cancers such as breast, cervical, gastric, colorectal, head and neck squamous cell, non-small-cell lung cancer, colon, prostate, oral and esophageal.[18][21][22][23][24] High expression levels are usually seen before the tumor cells become immortalized and aneuploid which can contribute to the chromosomal instability and the aggressive nature of certain cancers.[25] These high levels of cyclin B1 can also be associated to the extent of tumor invasion and aggressiveness therefore concentration of cyclin B1 can be used to determine the prognosis of cancer patients.[21][26] For example, an increase in expression of cyclin B1/cdc2 is significantly higher in breast tumor tissue and shown to increase lymph node metastasis in breast cancer.[21][27]

Cyclin B1 can reside in the nucleus or the cytoplasm which can have an effect on the malignant potential of cyclin B1 when overexpressed in each location. Nuclear-dominant expression of cyclin B1 leads to poorer prognosis due to its weak activity compared to cytoplasmic cyclin B1.[25] This trend has been observed in esophageal cancer, head and neck squamous cell cancer and breast cancer.[18][28]

Down regulation and tumor suppression

While the exact mechanism that explains how cyclin B1 becomes overexpressed is not very well understood, previous work has shown that down regulation of cyclin B1 can lead to tumor regression. A possible treatment option for tumor suppression is to deliver gene or protein to target the degradation of cyclin B1. Previous work done has shown that cyclin B1 is essential for tumor cell survival and proliferation and that a decrease in expression levels only leads to tumor-specific and not normal cell death.[29] Reduction of cyclin B1 can stop cells in the G2 phase of the cell cycle and triggers cell death by preventing the chromosomes from condensing and aligning. The specific downregulation of cyclin B1, however, did not influence other molecules that facilitated the transition from the G2 to M phase such as Cdk1, Cdc25c, Plk1 and cyclin A. Therefore the delivery of a therapeutic gene to correct these mutations is a viable treatment option for tumor suppression.[18]

Tumor antigen

In early stages of cancer when the cyclin B1 concentration is high, it is recognized by the immune system, leading to the production of antibodies and T cells. It would then be possible to take advantage of this to monitor the immune response for early cancer detection.[30] An ELISA (Enzyme-linked immunosorbent assay) can be performed to the measure the antibodies recognizing cyclin B1.

Breast cancer

Cyclin B1 expression levels can be used as a tool to determine prognosis of patients with breast cancers. The intracellular concentration can have important implications for cancer prognosis. High levels of nuclear cyclin B1 is associated with high tumor grade, larger tumor size and higher metastasis probability, therefore a high level of cyclin B1 is a predictor of poor prognosis.[25]

Lung cancer

Studies in non-small cell lung cancer demonstrated that high levels of cyclin B1 are associated with poorer prognosis. The study also found that this correlation between expression levels was only found in patients with squamous cell carcinoma. This finding indicates the possibility of using cyclin B1 expression as a prognostic marker for patients with early stage non-small cell lung cancer.[31]

See also

• Cyclin B

References

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11. Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E (February 1999). "Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest". Mol. Cell. Biol. 19 (2): 1460–9. doi:10.1128/mcb.19.2.1460. PMC 116074. PMID 9891079.
12. Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, Wang XW (November 2000). "Identification of a functional domain in a GADD45-mediated G2/M checkpoint". J. Biol. Chem. 275 (47): 36892–8. doi:10.1074/jbc.M005319200. PMID 10973963.
13. Pines, Jonathon; Hunter, Tony (1989). "Isolation of a human cyclin cDNA: Evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2". Cell. 58 (5): 833–846. doi:10.1016/0092-8674(89)90936-7. PMID 2570636.
14. Kong M, Barnes EA, Ollendorff V, Donoghue DJ (March 2000). "Cyclin F regulates the nuclear localization of cyclin B1 through a cyclin-cyclin interaction". EMBO J. 19 (6): 1378–88. doi:10.1093/emboj/19.6.1378. PMC 305678. PMID 10716937.
15. Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ (May 1999). "Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45". Oncogene. 18 (18): 2892–900. doi:10.1038/sj.onc.1202667. PMID 10362260.
16. Vairapandi M, Balliet AG, Hoffman B, Liebermann DA (September 2002). "GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress". J. Cell. Physiol. 192 (3): 327–38. doi:10.1002/jcp.10140. PMID 12124778.
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20. Innocente SA, Abrahamson JL, Cogswell JP, Lee JM (March 1999). "p53 regulates a G2 checkpoint through cyclin B1". Proc. Natl. Acad. Sci. U.S.A. 96 (5): 2147–52. Bibcode:1999PNAS...96.2147I. doi:10.1073/pnas.96.5.2147. PMC 26751. PMID 10051609.
21. Kawamoto H, Koizumi H, Uchikoshi T (January 1997). "Expression of the G2-M checkpoint regulators cyclin B1 and cdc2 in nonmalignant and malignant human breast lesions: immunocytochemical and quantitative image analyses". Am. J. Pathol. 150 (1): 15–23. PMC 1858517. PMID 9006317.
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24. Kushner J, Bradley G, Young B, Jordan RC (February 1999). "Aberrant expression of cyclin A and cyclin B1 proteins in oral carcinoma". J. Oral Pathol. Med. 28 (2): 77–81. doi:10.1111/j.1600-0714.1999.tb02000.x. PMID 9950254.
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Further reading

• Kino T, Chrousos GP (2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Ann. N. Y. Acad. Sci. 1024 (1): 153–67. Bibcode:2004NYASA1024..153K. doi:10.1196/annals.1321.013. PMID 15265780.
• Bailly E, Pines J, Hunter T, Bornens M (1992). "Cytoplasmic accumulation of cyclin B1 in human cells: association with a detergent-resistant compartment and with the centrosome". J. Cell Sci. 101 (3): 529–45. PMID 1387877.
• Galaktionov K, Beach D (1991). "Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins". Cell. 67 (6): 1181–94. doi:10.1016/0092-8674(91)90294-9. PMID 1836978.
• Pines J, Hunter T (1989). "Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2". Cell. 58 (5): 833–46. doi:10.1016/0092-8674(89)90936-7. PMID 2570636.
• He J, Choe S, Walker R, Di Marzio P, Morgan DO, Landau NR (1995). "Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity". J. Virol. 69 (11): 6705–11. PMC 189580. PMID 7474080.
• Re F, Braaten D, Franke EK, Luban J (1995). "Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin B". J. Virol. 69 (11): 6859–64. PMC 189600. PMID 7474100.
• Di Marzio P, Choe S, Ebright M, Knoblauch R, Landau NR (1995). "Mutational analysis of cell cycle arrest, nuclear localization and virion packaging of human immunodeficiency virus type 1 Vpr". J. Virol. 69 (12): 7909–16. PMC 189735. PMID 7494303.
• Jowett JB, Planelles V, Poon B, Shah NP, Chen ML, Chen IS (1995). "The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle". J. Virol. 69 (10): 6304–13. PMC 189529. PMID 7666531.
• Jackman M, Firth M, Pines J (1995). "Human cyclins B1 and B2 are localized to strikingly different structures: B1 to microtubules, B2 primarily to the Golgi apparatus". EMBO J. 14 (8): 1646–54. doi:10.1002/j.1460-2075.1995.tb07153.x. PMC 398257. PMID 7737117.
• Piaggio G, Farina A, Perrotti D, Manni I, Fuschi P, Sacchi A, Gaetano C (1995). "Structure and growth-dependent regulation of the human cyclin B1 promoter". Exp. Cell Res. 216 (2): 396–402. doi:10.1006/excr.1995.1050. PMID 7843284.
• Ookata K, Hisanaga S, Bulinski JC, Murofushi H, Aizawa H, Itoh TJ, Hotani H, Okumura E, Tachibana K, Kishimoto T (1995). "Cyclin B interaction with microtubule-associated protein 4 (MAP4) targets p34cdc2 kinase to microtubules and is a potential regulator of M-phase microtubule dynamics". J. Cell Biol. 128 (5): 849–62. doi:10.1083/jcb.128.5.849. PMC 2120387. PMID 7876309.
• Pines J, Hunter T (1994). "The differential localization of human cyclins A and B is due to a cytoplasmic retention signal in cyclin B". EMBO J. 13 (16): 3772–81. doi:10.1002/j.1460-2075.1994.tb06688.x. PMC 395290. PMID 8070405.
• Xiong Y, Zhang H, Beach D (1993). "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation" (PDF). Genes Dev. 7 (8): 1572–83. doi:10.1101/gad.7.8.1572. PMID 8101826.
• Zheng XF, Ruderman JV (1993). "Functional analysis of the P box, a domain in cyclin B required for the activation of Cdc25". Cell. 75 (1): 155–64. doi:10.1016/S0092-8674(05)80092-3. PMID 8402895.
• O'Connor PM, Ferris DK, Pagano M, Draetta G, Pines J, Hunter T, Longo DL, Kohn KW (1993). "G2 delay induced by nitrogen mustard in human cells affects cyclin A/cdk2 and cyclin B1/cdc2-kinase complexes differently". J. Biol. Chem. 268 (11): 8298–308. PMID 8463339.
• Sebastian B, Kakizuka A, Hunter T (1993). "Cdc25M2 activation of cyclin-dependent kinases by dephosphorylation of threonine-14 and tyrosine-15". Proc. Natl. Acad. Sci. U.S.A. 90 (8): 3521–4. Bibcode:1993PNAS...90.3521S. doi:10.1073/pnas.90.8.3521. PMC 46332. PMID 8475101.
• Kolesnitchenko V, Wahl LM, Tian H, Sunila I, Tani Y, Hartmann DP, Cossman J, Raffeld M, Orenstein J, Samelson LE, Cohen DI (1995). "Human immunodeficiency virus 1 envelope-initiated G2-phase programmed cell death". Proc. Natl. Acad. Sci. U.S.A. 92 (25): 11889–93. Bibcode:1995PNAS...9211889K. doi:10.1073/pnas.92.25.11889. PMC 40508. PMID 8524869.
• Poon RY, Jiang W, Toyoshima H, Hunter T (1996). "Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage". J. Biol. Chem. 271 (22): 13283–91. doi:10.1074/jbc.271.22.13283. PMID 8662825.
• Chen J, Saha P, Kornbluth S, Dynlacht BD, Dutta A (1996). "Cyclin-binding motifs are essential for the function of p21CIP1". Mol. Cell. Biol. 16 (9): 4673–82. doi:10.1128/MCB.16.9.4673. PMC 231467. PMID 8756624.