* 602755

CYCLIN B2; CCNB2


HGNC Approved Gene Symbol: CCNB2

Cytogenetic location: 15q22.2     Genomic coordinates (GRCh38): 15:59,105,146-59,125,045 (from NCBI)


TEXT

Description

Key events in the cell cycle are regulated by cyclin-dependent kinases (CDKs; see 116940), which are activated by binding a cyclin. B-type cyclins, such as CCNB2, contain a conserved cyclin box of approximately 100 amino acids that interacts with CDKs. In somatic cells, B-type cyclins accumulate through late S and G2 phases of the cell cycle in complex with CDK1 (summary by Jackman et al., 1995).


Cloning and Expression

By Western blot analysis of synchronized HeLa cells, Jackman et al. (1995) detected cyclin B2 at an apparent molecular mass of 48 kD, with peak expression in mitosis and undetectable expression in G1. Immunofluorescence analysis of several human cell lines at interphase detected cyclin B2 staining of intracellular membrane structures, including Golgi apparatus, and punctate structures throughout the cytoplasm. Intensity of staining increased through S and G2 phase. In prophase, cyclin B2 became dispersed throughout the cytoplasm, with a small fraction associated with the spindle apparatus. In contrast, cyclin B1 (CCNB1; 123836) localized to microtubules in interphase, and the authors noted that it had been reported to translocate to the nucleus at the beginning of prophase. Based on its dynamic intracellular localization during the cell cycle, Jackman et al. (1995) theorized that cyclin B2 might regulate membrane traffic during mitosis.

Scott (1998) noted that human ESTs homologous to mouse cyclin B2 can be found in GenBank.

Using the cytoplasmic domain of TGF-beta receptor-2 (TGFBR2; 190182) as bait in a yeast 2-hybrid screen of transformed human B cells, Liu et al. (1999) obtained a clone encoding a truncated form of cyclin B2. The truncated isoform lacks the 151 N-terminal amino acids of the full-length 398-amino acid protein, but it retains the central cyclin box. Northern blot analysis detected a 1.7-kb cyclin B2 transcript in all proliferating cell lines examined and in activated peripheral blood mononuclear cells (PBMCs), but not in resting PBMCs.


Mapping

Hartz (2014) mapped the CCNB2 gene to chromosome 15q22.2 based on an alignment of the CCNB2 sequence (GenBank AF002822) with the genomic sequence (GRCh37).


Gene Function

Using immunoprecipitation analysis and protein pull-down assays, Liu et al. (1999) confirmed direct interaction between TGFBR2 and the N-terminally truncated cyclin B2 isoform they identified through yeast 2-hybrid analysis. Full-length cyclin B2 bound TGFBR2 weakly compared with the truncated isoform. Binding analysis using cyclin B2 deletion mutants showed that full-length cyclin B2 contains a negative regulatory region immediately upstream of the cyclin box that inhibits TGFBR2 binding, and localized the TGFBR2-binding region to the C-terminal 134 amino acids. CDC2 (CDK1) associated with the receptor-cyclin B2 complex. In human THP-1 monocytic cells, TGF-beta (TGFB1; 190180) treatment enhanced all interactions and caused threonine phosphorylation of CDC2 in the complex, inhibiting the kinase activity of CDC2. Liu et al. (1999) concluded that TGF-beta can arrest cells at the G1/S boundary by inactivating cyclin B2-CDC2, which is required for exiting G1/S phase and entering G2/M.

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. Lagging chromosomes in Ccnb2-overexpressing cells correlated with abnormal spindle geometry, accelerated centrosome separation, and chromosome missegregation. Ccnb2 overexpression led to aurora kinase A (AURKA; 603072)-dependent hyperactivation of Plk1 (602098), which plays a role in disengaging and separating centrosomes. Inhibition of Plk1 or Aurka largely corrected Plk1 hyperactivation, spindle geometry defects, and chromosome missegregation, and also reduced aneuploidy. Knockdown of Ccnb2 in wildtype human and mouse cells led to centrosome nondisjunction and reduced levels of phosphorylated Plk1 and Aurka. Nam and van Deursen (2014) observed that overexpression of Ccnb2 or deletion of p53 (TP53; 191170) had identical effects on activation of Aurka, spindle geometry, and chromosome missegregation, and proposed that Ccnb2 and p53 antagonistically regulate centrosome separation.


Animal Model

Brandeis et al. (1998) noted that proliferating cells express both cyclins B1 and B2, which bind to and activate p34(CDC2). To test whether the 2 B-type cyclins have distinct roles, Brandeis et al. (1998) generated 2 lines of mutant 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 expression of cyclin B1 overlapped expression of cyclin B2 in the mature testis, but not vice versa. Cyclin B1 could be found both on intracellular membranes and free in the cytoplasm, in contrast with cyclin B2, which was membrane associated. These observations suggested that cyclin B1 may have compensated for the loss of cyclin B2 in the mutant mice, and implied that cyclin B1 is capable of targeting the p34(CDC2) kinase to the essential substrates of cyclin B2.


REFERENCES

  1. 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, images, related citations] [Full Text]

  2. Hartz, P. A. Personal Communication. Baltimore, Md. 7/22/2014.

  3. Jackman, M., Firth, M., Pines, J. Human cyclins B1 and B2 are localized to strikingly different structures: B1 to microtubules, B2 primarily to the Golgi apparatus. EMBO J. 14: 1646-1654, 1995. [PubMed: 7737117, related citations] [Full Text]

  4. Liu, J. H., Wei, S., Burnette, P. K., Gamero, A. M., Hutton, M., Djeu, J. Y. Functional association of TGF-beta receptor II with cyclin B. Oncogene 18: 269-275, 1999. [PubMed: 9926943, related citations] [Full Text]

  5. Nam, H.-J., van Deursen, J. M. Cyclin B2 and p53 control proper timing of centrosome separation. Nature Cell Biol. 16: 535-546, 2014.

  6. Scott, A. F. Personal Communication. Baltimore, Md. 6/25/1998.


Contributors:
Patricia A. Hartz - updated : 7/22/2014
Creation Date:
Victor A. McKusick : 6/25/1998
mgross : 10/13/2014
mgross : 10/13/2014
mcolton : 7/22/2014
mgross : 10/7/2003
carol : 2/26/1999
alopez : 6/25/1998
alopez : 6/25/1998

* 602755

CYCLIN B2; CCNB2


HGNC Approved Gene Symbol: CCNB2

Cytogenetic location: 15q22.2     Genomic coordinates (GRCh38): 15:59,105,146-59,125,045 (from NCBI)


TEXT

Description

Key events in the cell cycle are regulated by cyclin-dependent kinases (CDKs; see 116940), which are activated by binding a cyclin. B-type cyclins, such as CCNB2, contain a conserved cyclin box of approximately 100 amino acids that interacts with CDKs. In somatic cells, B-type cyclins accumulate through late S and G2 phases of the cell cycle in complex with CDK1 (summary by Jackman et al., 1995).


Cloning and Expression

By Western blot analysis of synchronized HeLa cells, Jackman et al. (1995) detected cyclin B2 at an apparent molecular mass of 48 kD, with peak expression in mitosis and undetectable expression in G1. Immunofluorescence analysis of several human cell lines at interphase detected cyclin B2 staining of intracellular membrane structures, including Golgi apparatus, and punctate structures throughout the cytoplasm. Intensity of staining increased through S and G2 phase. In prophase, cyclin B2 became dispersed throughout the cytoplasm, with a small fraction associated with the spindle apparatus. In contrast, cyclin B1 (CCNB1; 123836) localized to microtubules in interphase, and the authors noted that it had been reported to translocate to the nucleus at the beginning of prophase. Based on its dynamic intracellular localization during the cell cycle, Jackman et al. (1995) theorized that cyclin B2 might regulate membrane traffic during mitosis.

Scott (1998) noted that human ESTs homologous to mouse cyclin B2 can be found in GenBank.

Using the cytoplasmic domain of TGF-beta receptor-2 (TGFBR2; 190182) as bait in a yeast 2-hybrid screen of transformed human B cells, Liu et al. (1999) obtained a clone encoding a truncated form of cyclin B2. The truncated isoform lacks the 151 N-terminal amino acids of the full-length 398-amino acid protein, but it retains the central cyclin box. Northern blot analysis detected a 1.7-kb cyclin B2 transcript in all proliferating cell lines examined and in activated peripheral blood mononuclear cells (PBMCs), but not in resting PBMCs.


Mapping

Hartz (2014) mapped the CCNB2 gene to chromosome 15q22.2 based on an alignment of the CCNB2 sequence (GenBank AF002822) with the genomic sequence (GRCh37).


Gene Function

Using immunoprecipitation analysis and protein pull-down assays, Liu et al. (1999) confirmed direct interaction between TGFBR2 and the N-terminally truncated cyclin B2 isoform they identified through yeast 2-hybrid analysis. Full-length cyclin B2 bound TGFBR2 weakly compared with the truncated isoform. Binding analysis using cyclin B2 deletion mutants showed that full-length cyclin B2 contains a negative regulatory region immediately upstream of the cyclin box that inhibits TGFBR2 binding, and localized the TGFBR2-binding region to the C-terminal 134 amino acids. CDC2 (CDK1) associated with the receptor-cyclin B2 complex. In human THP-1 monocytic cells, TGF-beta (TGFB1; 190180) treatment enhanced all interactions and caused threonine phosphorylation of CDC2 in the complex, inhibiting the kinase activity of CDC2. Liu et al. (1999) concluded that TGF-beta can arrest cells at the G1/S boundary by inactivating cyclin B2-CDC2, which is required for exiting G1/S phase and entering G2/M.

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. Lagging chromosomes in Ccnb2-overexpressing cells correlated with abnormal spindle geometry, accelerated centrosome separation, and chromosome missegregation. Ccnb2 overexpression led to aurora kinase A (AURKA; 603072)-dependent hyperactivation of Plk1 (602098), which plays a role in disengaging and separating centrosomes. Inhibition of Plk1 or Aurka largely corrected Plk1 hyperactivation, spindle geometry defects, and chromosome missegregation, and also reduced aneuploidy. Knockdown of Ccnb2 in wildtype human and mouse cells led to centrosome nondisjunction and reduced levels of phosphorylated Plk1 and Aurka. Nam and van Deursen (2014) observed that overexpression of Ccnb2 or deletion of p53 (TP53; 191170) had identical effects on activation of Aurka, spindle geometry, and chromosome missegregation, and proposed that Ccnb2 and p53 antagonistically regulate centrosome separation.


Animal Model

Brandeis et al. (1998) noted that proliferating cells express both cyclins B1 and B2, which bind to and activate p34(CDC2). To test whether the 2 B-type cyclins have distinct roles, Brandeis et al. (1998) generated 2 lines of mutant 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 expression of cyclin B1 overlapped expression of cyclin B2 in the mature testis, but not vice versa. Cyclin B1 could be found both on intracellular membranes and free in the cytoplasm, in contrast with cyclin B2, which was membrane associated. These observations suggested that cyclin B1 may have compensated for the loss of cyclin B2 in the mutant mice, and implied that cyclin B1 is capable of targeting the p34(CDC2) kinase to the essential substrates of cyclin B2.


REFERENCES

  1. 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]

  2. Hartz, P. A. Personal Communication. Baltimore, Md. 7/22/2014.

  3. Jackman, M., Firth, M., Pines, J. Human cyclins B1 and B2 are localized to strikingly different structures: B1 to microtubules, B2 primarily to the Golgi apparatus. EMBO J. 14: 1646-1654, 1995. [PubMed: 7737117] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb07153.x]

  4. Liu, J. H., Wei, S., Burnette, P. K., Gamero, A. M., Hutton, M., Djeu, J. Y. Functional association of TGF-beta receptor II with cyclin B. Oncogene 18: 269-275, 1999. [PubMed: 9926943] [Full Text: https://doi.org/10.1038/sj.onc.1202263]

  5. Nam, H.-J., van Deursen, J. M. Cyclin B2 and p53 control proper timing of centrosome separation. Nature Cell Biol. 16: 535-546, 2014.

  6. Scott, A. F. Personal Communication. Baltimore, Md. 6/25/1998.


Contributors:
Patricia A. Hartz - updated : 7/22/2014

Creation Date:
Victor A. McKusick : 6/25/1998

Edit History:
mgross : 10/13/2014
mgross : 10/13/2014
mcolton : 7/22/2014
mgross : 10/7/2003
carol : 2/26/1999
alopez : 6/25/1998
alopez : 6/25/1998