Cyclin B is a member of the cyclin family. Cyclin B is a mitotic cyclin. The amount of cyclin B (which binds to Cdk1) and the activity of the cyclin B-Cdk complex rise through the cell cycle[2] until mitosis, where they fall abruptly due to degradation of cyclin B (Cdk1 is constitutively present).[3] The complex of Cdk and cyclin B is called maturation promoting factor or mitosis promoting factor (MPF).
| cyclin B1 | |||||||
|---|---|---|---|---|---|---|---|
 Structure of human cyclin B.[1] | |||||||
| Identifiers | |||||||
| Symbol | CCNB1 | ||||||
| Alt. symbols | CCNB | ||||||
| NCBI gene | 891 | ||||||
| HGNC | 1579 | ||||||
| OMIM | 123836 | ||||||
| RefSeq | NM_031966 | ||||||
| UniProt | P14635 | ||||||
| Other data | |||||||
| Locus | Chr. 5 q12 | ||||||
| |||||||
| cyclin B2 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | CCNB2 | ||||||
| NCBI gene | 9133 | ||||||
| HGNC | 1580 | ||||||
| OMIM | 602755 | ||||||
| RefSeq | NM_004701 | ||||||
| UniProt | O95067 | ||||||
| Other data | |||||||
| Locus | Chr. 15 q21.3 | ||||||
| |||||||
| cyclin B3 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | CCNB3 | ||||||
| NCBI gene | 85417 | ||||||
| HGNC | 18709 | ||||||
| OMIM | 300456 | ||||||
| RefSeq | NM_033670 | ||||||
| UniProt | Q8WWL7 | ||||||
| Other data | |||||||
| Locus | Chr. X p11 | ||||||
| |||||||
Function
editCyclin B is necessary for the progression of the cells into and out of M phase of the cell cycle.
At the end of S phase the phosphatase cdc25c dephosphorylates tyrosine15 and this activates the cyclin B/CDK1 complex. Upon activation the complex is shuttled to the nucleus where it serves to trigger for entry into mitosis.[4] However, if DNA damage is detected alternative proteins are activated which results in the inhibitory phosphorylation of cdc25c and therefore cyclinB/CDK1 is not activated. In order for the cell to progress out of mitosis, the degradation of cyclin B is necessary.[5]
The cyclin B/CDK1 complex also interacts with a variety of other key proteins and pathways which regulate cell growth and progression of mitosis. Cross-talk between many of these pathways links cyclin B levels indirectly to induction of apoptosis. The cyclin B/CDK1 complex plays a critical role in the expression of the survival signal survivin. Survivin is necessary for proper creation of the mitotic spindle which strongly affects cell viability, therefore when cyclin B levels are disrupted cells experience difficulty polarizing.[6] A decrease in survivin levels and the associated mitotic disarray triggers apoptosis via caspase 3 mediated pathway.
Role in Cancer
editCyclin B plays an integral role in many types of cancer. Hyperplasia (uncontrolled cell growth) is one of the hallmarks of cancer. Because cyclin B is necessary for cells to enter mitosis and therefore necessary for cell division, cyclin B levels are often de-regulated in tumors.[citation needed] When cyclin B levels are elevated, cells can enter M phase prematurely and strict control over cell division is lost, which is a favorable condition for cancer development. On the other hand, if cyclin B levels are depleted the cyclin B/CDK1 complex cannot form, cells cannot enter M phase and cell division slows down. Some anti-cancer therapies have been designed to prevent cyclin B/CDK1 complex formation in cancer cells to slow or prevent cell division. Most of these methods have _targeted the CDK1 subunit, but there is an emerging interest in the oncology field to _target cyclin B as well.
As a Biomarker
editCyclin levels can easily be determined through immunohistological analysis of tumor biopsies. The fact that cyclin B is often disregulated in cancer cells makes cyclin B an attractive biomarker. Many studies have been performed to examine cyclin levels in tumors, and it has been shown that levels of cyclin B is a strong indicator of prognosis in many types of cancer.[7] Generally, elevated levels of cyclin B are indicative of more aggressive cancers and a poor prognosis. Immunohistologically assessed levels of cyclin B could determine if women with stage 1, node negative, hormone receptor positive breast cancer were likely to benefit from adjuvant therapy.[8] In general women with this cancer have a very good prognosis, with mortality in 10 years of only 5%. Therefore, it is rare for oncologists to recommend adjuvant chemotherapy in these cases. However, in a small subset of patient this type of cancer is unexpectedly aggressive. These rare patients can be identified through their elevated cyclin B levels. In addition high levels of cyclin B also indicate poor prognosis and lymph node metastasis in gastric cancers.[9] However, not all cancers which overexpress cyclin B are more aggressive. A study in 2009 found that cyclin B overexpression in ovarian cancer indicates that the cancer is unlikely to be malignant while more aggressive ovarian cancers of epithelial cell origin do not show elevated cyclin B.[10]
Cyclin B and p53
editThere is strong cross-talk between the pathways regulating cyclin B and the tumor suppressor gene p53. In general levels of p53 and cyclin B are negatively correlated. When p53 build-up triggers cell cycle arrest the levels of downstream proteins p21 and WAF1 are increased which prevents cyclinB/CDK1 complex activation and therefore progression through the cell cycle.[11] It has also been observed that decreasing cyclin B levels in cells increases the levels of functional p53.[12] Therefore, siRNAs for cyclin B may be an effective treatment against cancers where p53 function is inhibited but the gene has not been deleted. In such cases lowering cyclin B levels restores the tumor suppressing function of p53 and also prevents cancer cells from dividing as a consequence of low cyclin B.
See also
editReferences
edit- ^ PDB: 2B9R; Petri, E.T.; Errico, A.; Escobedo, L.; Hunt, T. & Basavappa, R. (2007). "The crystal structure of human cyclin B". Cell Cycle. 6 (11): 1342–9. doi:10.4161/cc.6.11.4297. PMID 17495533.
- ^ Ito M (August 2000). "Factors controlling cyclin B expression" (PDF). Plant Mol. Biol. 43 (5–6): 677–90. doi:10.1023/A:1006336005587. PMID 11089869. S2CID 19593310.[permanent dead link]
- ^ Hershko A (September 1999). "Mechanisms and regulation of the degradation of cyclin B". Philos. Trans. R. Soc. Lond. B Biol. Sci. 354 (1389): 1571–5, discussion 1575–6. doi:10.1098/rstb.1999.0500. PMC 1692665. PMID 10582242.
- ^ Ford HL, Pardee AB (1999). "Cancer and the cell cycle". J. Cell. Biochem. Suppl 32-33 (S32): 166–72. doi:10.1002/(SICI)1097-4644(1999)75:32+<166::AID-JCB20>3.0.CO;2-J. PMID 10629116. S2CID 30299363.
- ^ Zhou XY, Wang X, Hu B, Guan J, Iliakis G, Wang Y (March 2002). "An ATM-independent S-phase checkpoint response involves CHK1 pathway". Cancer Res. 62 (6): 1598–603. PMID 11912127.
- ^ O'Connor DS, Wall NR, Porter AC, Altieri DC (July 2002). "A p34(cdc2) survival checkpoint in cancer". Cancer Cell. 2 (1): 43–54. doi:10.1016/S1535-6108(02)00084-3. PMID 12150824.
- ^ Agarwal R, Gonzalez-Angulo AM, Myhre S, Carey M, Lee JS, Overgaard J, Alsner J, Stemke-Hale K, Lluch A, Neve RM, Kuo WL, Sorlie T, Sahin A, Valero V, Keyomarsi K, Gray JW, Borresen-Dale AL, Mills GB, Hennessy BT (June 2009). "Integrative analysis of cyclin protein levels identifies cyclin b1 as a classifier and predictor of outcomes in breast cancer". Clin. Cancer Res. 15 (11): 3654–62. doi:10.1158/1078-0432.CCR-08-3293. PMC 2887710. PMID 19470724.
- ^ Koliadi A, Nilsson C, Holmqvist M, Holmberg L, de La Torre M, Wärnberg F, Fjällskog ML (August 2010). "Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer". Acta Oncol. 49 (6): 816–20. doi:10.3109/02841861003691937. PMID 20307242. S2CID 24515902.
- ^ Begnami MD, Fregnani JH, Nonogaki S, Soares FA (August 2010). "Evaluation of cell cycle protein expression in gastric cancer: cyclin B1 expression and its prognostic implication". Hum. Pathol. 41 (8): 1120–7. doi:10.1016/j.humpath.2010.01.007. PMID 20334896.
- ^ Zheng H, Hu W, Deavers MT, Shen DY, Fu S, Li YF, Kavanagh JJ (October 2009). "Nuclear cyclin B1 is overexpressed in low-malignant-potential ovarian tumors but not in epithelial ovarian cancer". Am. J. Obstet. Gynecol. 201 (4): 367.e1–6. doi:10.1016/j.ajog.2009.05.021. PMID 19608149.
- ^ Nigam N, Prasad S, George J, Shukla Y (April 2009). "Lupeol induces p53 and cyclin-B-mediated G2/M arrest and _targets apoptosis through activation of caspase in mouse skin". Biochem. Biophys. Res. Commun. 381 (2): 253–8. doi:10.1016/j.bbrc.2009.02.033. PMID 19232320.
- ^ Kreis NN, Sanhaji M, Krämer A, Sommer K, Rödel F, Strebhardt K, Yuan J (October 2010). "Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells". Oncogene. 29 (41): 5591–603. doi:10.1038/onc.2010.290. PMID 20661218.
External links
edit- Cyclin+B at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Drosophila Cyclin B - The Interactive Fly