* 116940

CYCLIN-DEPENDENT KINASE 1; CDK1


Alternative titles; symbols

CELL DIVISION CYCLE 2, G1 TO S AND G2 TO M; CDC2
CELL CYCLE CONTROLLER CDC2
p34(CDC2)


HGNC Approved Gene Symbol: CDK1

Cytogenetic location: 10q21.2     Genomic coordinates (GRCh38): 10:60,778,331-60,794,852 (from NCBI)


TEXT

Description

Cyclin-dependent kinase-1 (CDK1; EC 2.7.11.22), also known as CDC2, is a catalytic subunit of a protein kinase complex, called the M-phase promoting factor, that induces entry into mitosis and is universal among eukaryotes. In the fission yeast Schizosaccharomyces pombe, the gene cdc2 is responsible for controlling the transition from G1 phase to the S phase and from the G2 phase to the M phase of the cell cycle (summary by Draetta et al., 1988).


Cloning and Expression

Lee and Nurse (1987) rescued the human homolog of the cdc2 gene by complementation of a yeast temperature-sensitive mutant deleted for cdc2 function. The human sequences were cloned and found to contain an open reading frame of about 800 bp.

Using the human CDC2 gene as a DNA probe, Spurr et al. (1990) isolated cDNA clones corresponding to the mouse cdc2 gene. The deduced amino acid sequence of the mouse protein showed 96% identity to its human homolog.


Gene Function

Lee et al. (1988) described the regulated expression and phosphorylation of the CDC2 homolog in human and murine in vitro systems. Whereas the yeast cdc2 expression does not appear to be transcriptionally regulated, serum stimulation of human and mouse fibroblasts results in a marked increase in CDC2 transcription. Both the yeast and mammalian systems seem to be regulated by phosphorylation of the CDC2 gene product, a protein kinase of molecular weight 34,000, designated p34(cdc2).

Draetta et al. (1988) showed that in HeLa cells CDC2 is the most abundant phosphotyrosine-containing protein and its phosphotyrosine content is subject to cell cycle regulation. One site of CDC2 tyrosine phosphorylation in vivo is selectively phosphorylated in vitro by a product of the SRC gene (190090). Liu et al. (1997) reported that the kinase MYT1 (602474) also phosphorylates CDC2.

Overexpression of the receptor tyrosine kinase ERBB2 (164870) confers Taxol resistance in breast cancers (114480). Yu et al. (1998) found that overexpression of ERBB2 inhibits Taxol-induced apoptosis. Taxol activates CDC2 kinase in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of CDC2 and a dominant-negative mutant of CDC2 blocked Taxol-induced apoptosis in these cells. Overexpression of ERBB2 in MDA-MB-435 cells by transfection transcriptionally upregulates CDKN1A (116899) which associates with CDC2, inhibits Taxol-mediated CDC2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In CDKN1A antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, ERBB2 was unable to inhibit Taxol-induced apoptosis. Therefore, CDKN1A participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in ERBB2-overexpressing breast cancer cells.

ERBB2 overexpression confers resistance to taxol-induced apoptosis by inhibiting p34(CDC2) activation. One mechanism is via ERBB2-mediated upregulation of p21(CIP1), or CDKN1A, which inhibits CDC2. Tan et al. (2002) reported that the inhibitory phosphorylation on tyr15 (Y15) of CDC2 was elevated in ERBB2-overexpressing breast cancer cells and primary tumors. ERBB2 bound to and colocalized with cyclin B (123836)-CDC2 complexes and phosphorylated CDC2 Y15. The ERBB2 kinase domain was sufficient to directly phosphorylate CDC2 Y15. Increased CDC2 with phosphorylated Y15 in ERBB2-overexpressing cells corresponded with delayed M phase entry. Expression of a nonphosphorylatable mutant of CDC2 rendered cells more sensitive to taxol-induced apoptosis. Thus, the authors concluded that ERBB2 can confer resistance to taxol-induced apoptosis by directly phosphorylating CDC2.

Konishi et al. (2002) reported that Cdc2 is expressed in postmitotic granule neurons of the developing rat cerebellum and that Cdc2 mediates apoptosis of cerebellar granule neurons upon the suppression of neuronal activity. They showed that Cdc2 catalyzes the phosphorylation of the BAD protein (603167) at a distinct site, ser128, and thereby induces BAD-mediated apoptosis in primary neurons by opposing growth factor inhibition of the apoptotic effect of BAD. Phosphorylation of BAD ser128 was found to inhibit the interaction of growth factor-induced ser136-phosphorylated BAD with 14-3-3 proteins (see 601288).

In higher eukaryotes, the S phase and M phase of the cell cycle are triggered by different cyclin-dependent kinases (CDKs). For example, in frog egg extracts, Cdk1-cyclin B catalyzes entry into mitosis but cannot trigger DNA replication. Two hypotheses can explain this observation: either Cdk1-cyclin B fails to recognize the key substrates of its S-phase-promoting counterparts, or its activity is somehow regulated to prevent it from activating DNA synthesis. Moore et al. (2003) demonstrated that Cdk1-cyclin B1 has cryptic S-phase-promoting abilities that can be unmasked by relocating it from the cytoplasm to the nucleus and moderately stimulating its activity with Cdc25 phosphatase (157680). Subcellular localization of vertebrate CDKs and the control of their activity are thus critical factors for determining their specificity.

Matsuo et al. (2003) studied the regenerating liver of mice and demonstrated that the circadian clock controls expression of cell cycle-related genes that in turn modulate the expression of active cyclin B1-Cdc2 kinase, a key regulator of mitosis. Among these genes, Matsuo et al. (2003) found that expression of Wee1 (193525) was directly regulated by the molecular components of the circadian clockwork. In contrast, the circadian clockwork oscillated independently of the cell cycle in single cells. Matsuo et al. (2003) concluded that the intracellular circadian clockwork can control the cell division cycle directly and unidirectionally in proliferating cells.

Li and Zheng (2004) provided evidence that CDC2 coordinates spindle assembly with the cell cycle during mitosis through phosphorylation of RCC1 (179710). CDC2 phosphorylates RCC1 on serines located in or near its nuclear localization signal. This phosphorylation activates RCC1 to generate RanGTP on mitotic chromosomes, which is required for spindle assembly and chromosome segregation.

Ira et al. (2004) reported that DNA damage checkpoint activation by a double-strand break requires the cyclin-dependent kinase Cdk1 (Cdc28) in budding yeast. Cdk1 is also required for double-strand break-induced homologous recombination at any cell cycle stage. Inhibition of homologous recombination by using an analog-sensitive Cdk1 protein resulted in a compensatory increase in nonhomologous end joining. Cdk1 is required for efficient 5-prime to 3-prime resection of double-strand break ends and for the recruitment of both the single-stranded DNA-binding complex, RPA, and the Rad51 (179617) recombination protein. In contrast, Mre11 protein (600814), part of the MRX complex, accumulates at unresected double-strand break ends. Cdk1 is not required when the DNA damage checkpoint is initiated by lesions that are processed by nucleotide excision repair. Maintenance of the double-strand break-induced checkpoint requires continuing Cdk1 activity that ensures continuing end resection. Cdk1 is also important for a later step in homologous recombination, after strand invasion and before the initiation of new DNA synthesis.

In yeast, double-strand break repair is regulated by the cell cycle through Cdk1. Frank et al. (2006) showed that telomere addition in yeast also required Cdk1 and the nuclease activity of Mre11. Cdk1 activity was required for the formation of the 3-prime single-strand overhang structure at both de novo and native telomeres.

Santamaria et al. (2007) showed that mouse embryos lacking all interphase Cdks (Cdk2, 116953, Cdk3, 123828, Cdk4, 123829, and Cdk6, 603368) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the Rb protein (614041) and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. The authors also reported that embryos failed to develop to the morula and blastocyst stages in the absence of Cdk1. Santamaria et al. (2007) concluded that CDK1 is the only essential cell cycle Cdk. Moreover, their data showed that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.

Goga et al. (2007) examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein survivin (BIRC5; 603352), a non-CDK target, was required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulated survivin expression and induced MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival.

Yuan et al. (2008) found that CDK1 phosphorylated the transcription factor FOXO1 (136533) at serine-249 in vitro and in vivo. The phosphorylation of FOXO1 at serine-249 disrupted FOXO1 binding with 14-3-3 (see 601289) proteins and thereby promoted the nuclear accumulation of FOXO1 and stimulated FOXO1-dependent transcription, leading to cell death in neurons. In proliferating cells, CDK1 induced FOXO1 serine-249 phosphorylation at the G2/M phase of the cell cycle, resulting in FOXO1-dependent expression of the mitotic regulator Polo-like kinase (Plk; 602098). Yuan et al. (2008) concluded that their findings defined a conserved signaling link between CDK1 and FOXO1 that may have a key role in diverse biologic processes including the degeneration of postmitotic neurons.

Anaphase is initiated when a ubiquitin ligase, the anaphase-promoting complex (APC; see 608473), triggers the destruction of securin (604147), thereby allowing separase (604143), a protease, to disrupt sister chromatid cohesion. Holt et al. (2008) demonstrated that the Cdk1-dependent phosphorylation of securin near its destruction-box motif inhibits securin ubiquitination by the APC. The phosphatase Cdc14 (603504) reverses securin phosphorylation, thereby increasing the rate of securin ubiquitination. Because separase is known to activate Cdc14, Holt et al. (2008) concluded that their results supported the existence of a positive feedback loop that increases the abruptness of anaphase. Consistent with this model, they showed that mutations that disrupt securin phosphoregulation decreased the synchrony of chromosome segregation. Holt et al. (2008) also concluded that coupling securin degradation with changes in Cdk1 and Cdc14 activities helps coordinate the initiation of sister chromatid separation with changes in spindle dynamics.

Tsukahara et al. (2010) isolated a fission yeast cyclin B (123836) mutant defective specifically in chromosome biorientation. Accordingly, Tsukahara et al. (2010) identified Cdk1-cyclin B-dependent phosphorylation of survivin. Preventing survivin phosphorylation impaired centromere chromosomal passenger complex (CPC) targeting as well as chromosome biorientation, whereas phosphomimetic survivin suppressed the biorientation defect in the cyclin B mutant. Survivin phosphorylation promoted direct binding with shugoshin (see 609168), which Tsukahara et al. (2010) defined as a conserved centromeric adaptor of the CPC. In human cells, the phosphorylation of borealin (609977) has a comparable role. Tsukahara et al. (2010) concluded that this study resolved the conserved mechanisms of CPC targeting to centromeres, highlighting a key role of Cdk1-cyclin B in chromosome biorientation.

Cdc2 inactivation by Wee1b (WEE2; 614084)-mediated phosphorylation is necessary for arrest of the oocyte at G2-prophase. Oh et al. (2011) showed that reactivation of a Wee1B pathway triggers the decrease in Cdc2 activity during egg activation. When Wee1B is downregulated, oocytes fail to form a pronucleus in response to calcium signals. Calcium-calmodulin-dependent kinase II (CaMKII; see 114078) activates Wee1B, and CaMKII-driven exit from metaphase II is inhibited by Wee1B downregulation, demonstrating that exit from metaphase requires not only a proteolytic degradation of cyclin B but also the inhibitory phosphorylation of Cdc2 by Wee1B.

Harbauer et al. (2014) found that CDK1 stimulated assembly of the main mitochondrial entry gate, the translocase of the outer membrane (TOM), in mitosis. In an S. cerevisiae assay, Harbauer et al. (2014) found that the molecular mechanism involves phosphorylation of the cytosolic precursor of TOM6 (616168) by cyclin CLB3-activated CDK1, leading to enhanced import of TOM6 into mitochondria. TOM6 phosphorylation promoted assembly of the protein import channel TOM40 (608061) and import of fusion proteins, thus stimulating the respiratory activity of mitochondria in mitosis. Harbauer et al. (2014) concluded that TOM6 phosphorylation provides a direct means for regulating mitochondrial biogenesis and activity in a cell cycle-specific manner.

Using systematic reconstitution and analysis of vertebrate anaphase-promoting complex/cyclosomes (APC/Cs) under physiologic conditions, Fujimitsu et al. (2016) showed how CDK1 activates the APC/C through coordinated phosphorylation between Apc3 (116946) and Apc1 (608473). Phosphorylation of the loop domains by CDK1 in complex with the CDK regulatory subunit p9/Cks2 (116901) controlled loading of coactivator Cdc20 (603618) onto APC/C. A phosphomimetic mutation introduced into Apc1 allowed Cdc20 to increase APC/C activity in interphase. These results defined a theretofore unrecognized subunit-subunit communication over a distance and the functional consequences of CDK phosphorylation.

The mitotic oscillator, centered on the CDK1-anaphase-promoting complex/cyclosome (CDK1-APC/C) axis, spatiotemporally coordinates organelle remodeling in dividing cells. Al Jord et al. (2017) discovered that nondividing cells could also implement this mitotic clocklike regulatory circuit to orchestrate subcellular reorganization associated with differentiation. Al Jord et al. (2017) probed centriole amplification in differentiating mouse brain multiciliated cells. These postmitotic progenitors fine-tuned mitotic oscillator activity to drive the orderly progression of centriole production, maturation, and motile ciliation while avoiding the mitosis commitment threshold. Insufficient CDK1 activity hindered differentiation, whereas excessive activity accelerated differentiation yet drove postmitotic progenitors into mitosis. Thus, Al Jord et al. (2017) concluded that postmitotic cells can redeploy and calibrate the mitotic oscillator to uncouple cytoplasmic from nuclear dynamics for organelle remodeling associated with differentiation.

Saldivar et al. (2018) demonstrated that cells transactivate the mitotic gene network as they exit the S phase through a CDK1-directed FOXM1 (602341) phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR (601215) is activated by ETAA1 (613196) to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint.


Mapping

Spurr et al. (1987, 1988) studied a panel of somatic cell hybrids and determined that the human homolog of the CDK1 gene is located on chromosome 10. By in situ hybridization, Nazarenko et al. (1991) regionalized the CDK1 gene to chromosome 10q21.


REFERENCES

  1. Al Jord, A., Shihavuddin, A., Servignat d'Aout, R., Faucourt, M., Genovesio, A., Karaiskou, A., Sobczak-Thepot, J., Spassky, N., Meunier, A. Calibrated mitotic oscillator drives motile ciliogenesis. Science 358: 803-806, 2017. [PubMed: 28982797, related citations] [Full Text]

  2. Draetta, G., Piwnica-Worms, H., Morrison, D., Druker, B., Roberts, T., Beach, D. Human CDC2 protein kinase is a major cell-cycle regulated tyrosine kinase substrate. Nature 336: 738-744, 1988. [PubMed: 2462672, related citations] [Full Text]

  3. Frank, C. J., Hyde, M., Greider, C. W. Regulation of telomere elongation by the cyclin-dependent kinase CDK1. Molec. Cell 24: 423-432, 2006. [PubMed: 17070718, related citations] [Full Text]

  4. Fujimitsu, K., Grimaldi, M., Yamano, H. Cyclin-dependent kinase 1-dependent activation of APC/C ubiquitin ligase. Science 352: 1121-1124, 2016. [PubMed: 27103671, related citations] [Full Text]

  5. Goga, A. Yang, D., Tward, A. D., Morgan, D. O., Bishop, J. M. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nature Med. 13: 820-827, 2007. [PubMed: 17589519, related citations] [Full Text]

  6. Harbauer, A. B., Opalinska, M., Gerbeth, C., Herman, J. S., Rao, S., Schonfisch, B., Guiard, B., Schmidt, O., Pfanner, N., Meisinger, C. Cell cycle-dependent regulation of mitochondrial preprotein translocase. Science 346: 1109-1113, 2014. [PubMed: 25378463, related citations] [Full Text]

  7. Holt, L. J., Krutchinsky, A. N., Morgan, D. O. Positive feedback sharpens the anaphase switch. Nature 454: 353-357, 2008. [PubMed: 18552837, images, related citations] [Full Text]

  8. Ira, G., Pellicioli, A., Balijja, A., Wang, X., Fiorani, S., Carotenuto, W., Liberi, G., Bressan, D., Wan, L., Hollingsworth, N. M., Haber, J. E., Foiani, M. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431: 1011-1017, 2004. [PubMed: 15496928, images, related citations] [Full Text]

  9. Konishi, Y., Lehtinen, M., Donovan, N., Bonni, A. Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Molec. Cell 9: 1005-1016, 2002. [PubMed: 12049737, related citations] [Full Text]

  10. Lee, M. G., Norbury, C. J., Spurr, N. K., Nurse, P. Regulated expression and phosphorylation of a possible mammalian cell-cycle control protein. (Letter) Nature 333: 676-679, 1988. [PubMed: 3287181, related citations] [Full Text]

  11. Lee, M. G., Nurse, P. Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 327: 31-35, 1987. [PubMed: 3553962, related citations] [Full Text]

  12. Li, H.-Y., Zheng, Y. Phosphorylation of RCC1 in mitosis is essential for producing a high RanGTP concentration on chromosomes and for spindle assembly in mammalian cells. Genes Dev. 18: 512-527, 2004. [PubMed: 15014043, images, related citations] [Full Text]

  13. Liu, F., Stanton, J. J., Wu, Z., Piwnica-Worms, H. The human myt1 kinase preferentially phosphorylates cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Molec. Cell. Biol. 17: 571-583, 1997. [PubMed: 9001210, related citations] [Full Text]

  14. Matsuo, T., Yamaguchi, S., Mitsui, S., Emi, A., Shimoda, F., Okamura, H. Control mechanism of the circadian clock for timing of cell division in vivo. Science 302: 255-259, 2003. [PubMed: 12934012, related citations] [Full Text]

  15. Moore, J. D., Kirk, J. A., Hunt, T. Unmasking the S-phase-promoting potential of cyclin B1. Science 300: 987-990, 2003. [PubMed: 12738867, related citations] [Full Text]

  16. Nazarenko, S. A., Ostroverhova, N. V., Spurr, N. K. Regional assignment of the human cell cycle control gene CDC2 to chromosome 10q21 by in situ hybridization. Hum. Genet. 87: 621-622, 1991. [PubMed: 1916766, related citations] [Full Text]

  17. Oh, J. S., Susor, A., Conti, M. Protein tyrosine kinase Wee1B is essential for metaphase II exit in mouse oocytes. Science 332: 462-465, 2011. [PubMed: 21454751, images, related citations] [Full Text]

  18. Saldivar, J. C., Hamperl, S., Bocek, M. J., Chung, M., Bass, T. E., Cisneros-Soberanis, F., Samejima, K., Xie, L., Paulson, J. R., Earnshaw, W. C., Cortez, D., Meyer, T., Cimprich, K. A. An intrinsic S/G2 checkpoint enforced by ATR. Science 361: 806-810, 2018. [PubMed: 30139873, related citations] [Full Text]

  19. Santamaria, D., Barriere, C., Cerqueira, A., Hunt, S., Tardy, C., Newton, K., Caceres, J. F., Dubus, P., Malumbres, M., Barbacid, M. Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448: 811-815, 2007. [PubMed: 17700700, related citations] [Full Text]

  20. Spurr, N. K., Goodfellow, P. N., Nurse, P., Lee, M. Assignment of the human homologue of the yeast cell cycle control gene CDC2 to chromosome 10. (Abstract) Cytogenet. Cell Genet. 46: 698, 1987.

  21. Spurr, N. K., Gough, A. C., Lee, M. G. Cloning of the mouse homologue of the yeast cell cycle control gene cdc2. DNA Seq. 1: 49-54, 1990. [PubMed: 2132958, related citations] [Full Text]

  22. Spurr, N. K., Gough, A., Goodfellow, P. J., Goodfellow, P. N., Lee, M. G., Nurse, P. Evolutionary conservation of the human homologue of the yeast cell cycle control gene cdc2 and assignment of CD2 to chromosome 10. Hum. Genet. 78: 333-337, 1988. [PubMed: 2896153, related citations] [Full Text]

  23. Tan, M., Jing, T., Lan, K.-H., Neal, C. L., Li, P., Lee, S., Fang, D., Nagata, Y., Liu, J., Arlinghaus, R., Hung, M.-C., Yu, D. Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis. Molec. Cell 9: 993-1004, 2002. [PubMed: 12049736, related citations] [Full Text]

  24. Tsukahara, T., Tanno, Y., Watanabe, Y. Phosphorylation of the CPC by Cdk1 promotes chromosome bi-orientation. Nature 467: 719-723, 2010. [PubMed: 20739936, related citations] [Full Text]

  25. Yu, D., Jing, T., Liu, B., Yao, J., Tan, M., McDonnell, T. J., Hung, M.-C. Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase. Molec. Cell 2: 581-591, 1998. [PubMed: 9844631, related citations] [Full Text]

  26. Yuan, Z., Becker, E. B. E., Merlo, P., Yamada, T., DiBacco, S., Konishi, Y., Schaefer, E. M., Bonni, E. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science 319: 1665-1668, 2008. [PubMed: 18356527, related citations] [Full Text]


Ada Hamosh - updated : 11/20/2018
Ada Hamosh - updated : 02/08/2018
Ada Hamosh - updated : 09/01/2016
Ada Hamosh - updated : 01/13/2015
Ada Hamosh - updated : 7/8/2011
Ada Hamosh - updated : 8/12/2008
Ada Hamosh - updated : 5/8/2008
Ada Hamosh - updated : 2/25/2008
Ada Hamosh - updated : 10/15/2007
Patricia A. Hartz - updated : 12/4/2006
Ada Hamosh - updated : 1/26/2005
Patricia A. Hartz - updated : 5/11/2004
Ada Hamosh - updated : 10/28/2003
Ada Hamosh - updated : 5/29/2003
Stylianos E. Antonarakis - updated : 9/18/2002
Jennifer P. Macke - updated : 5/27/1998
Creation Date:
Victor A. McKusick : 8/31/1987
carol : 06/19/2019
carol : 06/18/2019
alopez : 11/20/2018
alopez : 06/15/2018
alopez : 02/08/2018
alopez : 09/01/2016
alopez : 01/13/2015
alopez : 7/12/2011
alopez : 7/11/2011
terry : 7/8/2011
carol : 6/17/2011
alopez : 10/27/2010
alopez : 10/27/2010
wwang : 5/5/2010
alopez : 8/25/2008
alopez : 8/25/2008
terry : 8/12/2008
alopez : 5/19/2008
terry : 5/8/2008
alopez : 3/3/2008
terry : 2/25/2008
alopez : 10/26/2007
terry : 10/15/2007
wwang : 12/4/2006
tkritzer : 2/10/2005
terry : 1/26/2005
mgross : 5/11/2004
tkritzer : 10/29/2003
terry : 10/28/2003
terry : 5/29/2003
mgross : 9/18/2002
mgross : 9/18/2002
terry : 11/15/2001
joanna : 10/9/2001
carol : 2/10/1999
mgross : 2/9/1999
mgross : 2/9/1999
dholmes : 5/27/1998
dholmes : 5/27/1998
dholmes : 5/27/1998
dholmes : 4/16/1998
mark : 4/1/1996
carol : 5/6/1994
supermim : 3/16/1992
carol : 2/18/1992
carol : 11/4/1991
carol : 10/24/1991
carol : 10/23/1991

* 116940

CYCLIN-DEPENDENT KINASE 1; CDK1


Alternative titles; symbols

CELL DIVISION CYCLE 2, G1 TO S AND G2 TO M; CDC2
CELL CYCLE CONTROLLER CDC2
p34(CDC2)


HGNC Approved Gene Symbol: CDK1

Cytogenetic location: 10q21.2     Genomic coordinates (GRCh38): 10:60,778,331-60,794,852 (from NCBI)


TEXT

Description

Cyclin-dependent kinase-1 (CDK1; EC 2.7.11.22), also known as CDC2, is a catalytic subunit of a protein kinase complex, called the M-phase promoting factor, that induces entry into mitosis and is universal among eukaryotes. In the fission yeast Schizosaccharomyces pombe, the gene cdc2 is responsible for controlling the transition from G1 phase to the S phase and from the G2 phase to the M phase of the cell cycle (summary by Draetta et al., 1988).


Cloning and Expression

Lee and Nurse (1987) rescued the human homolog of the cdc2 gene by complementation of a yeast temperature-sensitive mutant deleted for cdc2 function. The human sequences were cloned and found to contain an open reading frame of about 800 bp.

Using the human CDC2 gene as a DNA probe, Spurr et al. (1990) isolated cDNA clones corresponding to the mouse cdc2 gene. The deduced amino acid sequence of the mouse protein showed 96% identity to its human homolog.


Gene Function

Lee et al. (1988) described the regulated expression and phosphorylation of the CDC2 homolog in human and murine in vitro systems. Whereas the yeast cdc2 expression does not appear to be transcriptionally regulated, serum stimulation of human and mouse fibroblasts results in a marked increase in CDC2 transcription. Both the yeast and mammalian systems seem to be regulated by phosphorylation of the CDC2 gene product, a protein kinase of molecular weight 34,000, designated p34(cdc2).

Draetta et al. (1988) showed that in HeLa cells CDC2 is the most abundant phosphotyrosine-containing protein and its phosphotyrosine content is subject to cell cycle regulation. One site of CDC2 tyrosine phosphorylation in vivo is selectively phosphorylated in vitro by a product of the SRC gene (190090). Liu et al. (1997) reported that the kinase MYT1 (602474) also phosphorylates CDC2.

Overexpression of the receptor tyrosine kinase ERBB2 (164870) confers Taxol resistance in breast cancers (114480). Yu et al. (1998) found that overexpression of ERBB2 inhibits Taxol-induced apoptosis. Taxol activates CDC2 kinase in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of CDC2 and a dominant-negative mutant of CDC2 blocked Taxol-induced apoptosis in these cells. Overexpression of ERBB2 in MDA-MB-435 cells by transfection transcriptionally upregulates CDKN1A (116899) which associates with CDC2, inhibits Taxol-mediated CDC2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In CDKN1A antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, ERBB2 was unable to inhibit Taxol-induced apoptosis. Therefore, CDKN1A participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in ERBB2-overexpressing breast cancer cells.

ERBB2 overexpression confers resistance to taxol-induced apoptosis by inhibiting p34(CDC2) activation. One mechanism is via ERBB2-mediated upregulation of p21(CIP1), or CDKN1A, which inhibits CDC2. Tan et al. (2002) reported that the inhibitory phosphorylation on tyr15 (Y15) of CDC2 was elevated in ERBB2-overexpressing breast cancer cells and primary tumors. ERBB2 bound to and colocalized with cyclin B (123836)-CDC2 complexes and phosphorylated CDC2 Y15. The ERBB2 kinase domain was sufficient to directly phosphorylate CDC2 Y15. Increased CDC2 with phosphorylated Y15 in ERBB2-overexpressing cells corresponded with delayed M phase entry. Expression of a nonphosphorylatable mutant of CDC2 rendered cells more sensitive to taxol-induced apoptosis. Thus, the authors concluded that ERBB2 can confer resistance to taxol-induced apoptosis by directly phosphorylating CDC2.

Konishi et al. (2002) reported that Cdc2 is expressed in postmitotic granule neurons of the developing rat cerebellum and that Cdc2 mediates apoptosis of cerebellar granule neurons upon the suppression of neuronal activity. They showed that Cdc2 catalyzes the phosphorylation of the BAD protein (603167) at a distinct site, ser128, and thereby induces BAD-mediated apoptosis in primary neurons by opposing growth factor inhibition of the apoptotic effect of BAD. Phosphorylation of BAD ser128 was found to inhibit the interaction of growth factor-induced ser136-phosphorylated BAD with 14-3-3 proteins (see 601288).

In higher eukaryotes, the S phase and M phase of the cell cycle are triggered by different cyclin-dependent kinases (CDKs). For example, in frog egg extracts, Cdk1-cyclin B catalyzes entry into mitosis but cannot trigger DNA replication. Two hypotheses can explain this observation: either Cdk1-cyclin B fails to recognize the key substrates of its S-phase-promoting counterparts, or its activity is somehow regulated to prevent it from activating DNA synthesis. Moore et al. (2003) demonstrated that Cdk1-cyclin B1 has cryptic S-phase-promoting abilities that can be unmasked by relocating it from the cytoplasm to the nucleus and moderately stimulating its activity with Cdc25 phosphatase (157680). Subcellular localization of vertebrate CDKs and the control of their activity are thus critical factors for determining their specificity.

Matsuo et al. (2003) studied the regenerating liver of mice and demonstrated that the circadian clock controls expression of cell cycle-related genes that in turn modulate the expression of active cyclin B1-Cdc2 kinase, a key regulator of mitosis. Among these genes, Matsuo et al. (2003) found that expression of Wee1 (193525) was directly regulated by the molecular components of the circadian clockwork. In contrast, the circadian clockwork oscillated independently of the cell cycle in single cells. Matsuo et al. (2003) concluded that the intracellular circadian clockwork can control the cell division cycle directly and unidirectionally in proliferating cells.

Li and Zheng (2004) provided evidence that CDC2 coordinates spindle assembly with the cell cycle during mitosis through phosphorylation of RCC1 (179710). CDC2 phosphorylates RCC1 on serines located in or near its nuclear localization signal. This phosphorylation activates RCC1 to generate RanGTP on mitotic chromosomes, which is required for spindle assembly and chromosome segregation.

Ira et al. (2004) reported that DNA damage checkpoint activation by a double-strand break requires the cyclin-dependent kinase Cdk1 (Cdc28) in budding yeast. Cdk1 is also required for double-strand break-induced homologous recombination at any cell cycle stage. Inhibition of homologous recombination by using an analog-sensitive Cdk1 protein resulted in a compensatory increase in nonhomologous end joining. Cdk1 is required for efficient 5-prime to 3-prime resection of double-strand break ends and for the recruitment of both the single-stranded DNA-binding complex, RPA, and the Rad51 (179617) recombination protein. In contrast, Mre11 protein (600814), part of the MRX complex, accumulates at unresected double-strand break ends. Cdk1 is not required when the DNA damage checkpoint is initiated by lesions that are processed by nucleotide excision repair. Maintenance of the double-strand break-induced checkpoint requires continuing Cdk1 activity that ensures continuing end resection. Cdk1 is also important for a later step in homologous recombination, after strand invasion and before the initiation of new DNA synthesis.

In yeast, double-strand break repair is regulated by the cell cycle through Cdk1. Frank et al. (2006) showed that telomere addition in yeast also required Cdk1 and the nuclease activity of Mre11. Cdk1 activity was required for the formation of the 3-prime single-strand overhang structure at both de novo and native telomeres.

Santamaria et al. (2007) showed that mouse embryos lacking all interphase Cdks (Cdk2, 116953, Cdk3, 123828, Cdk4, 123829, and Cdk6, 603368) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the Rb protein (614041) and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. The authors also reported that embryos failed to develop to the morula and blastocyst stages in the absence of Cdk1. Santamaria et al. (2007) concluded that CDK1 is the only essential cell cycle Cdk. Moreover, their data showed that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.

Goga et al. (2007) examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein survivin (BIRC5; 603352), a non-CDK target, was required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulated survivin expression and induced MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival.

Yuan et al. (2008) found that CDK1 phosphorylated the transcription factor FOXO1 (136533) at serine-249 in vitro and in vivo. The phosphorylation of FOXO1 at serine-249 disrupted FOXO1 binding with 14-3-3 (see 601289) proteins and thereby promoted the nuclear accumulation of FOXO1 and stimulated FOXO1-dependent transcription, leading to cell death in neurons. In proliferating cells, CDK1 induced FOXO1 serine-249 phosphorylation at the G2/M phase of the cell cycle, resulting in FOXO1-dependent expression of the mitotic regulator Polo-like kinase (Plk; 602098). Yuan et al. (2008) concluded that their findings defined a conserved signaling link between CDK1 and FOXO1 that may have a key role in diverse biologic processes including the degeneration of postmitotic neurons.

Anaphase is initiated when a ubiquitin ligase, the anaphase-promoting complex (APC; see 608473), triggers the destruction of securin (604147), thereby allowing separase (604143), a protease, to disrupt sister chromatid cohesion. Holt et al. (2008) demonstrated that the Cdk1-dependent phosphorylation of securin near its destruction-box motif inhibits securin ubiquitination by the APC. The phosphatase Cdc14 (603504) reverses securin phosphorylation, thereby increasing the rate of securin ubiquitination. Because separase is known to activate Cdc14, Holt et al. (2008) concluded that their results supported the existence of a positive feedback loop that increases the abruptness of anaphase. Consistent with this model, they showed that mutations that disrupt securin phosphoregulation decreased the synchrony of chromosome segregation. Holt et al. (2008) also concluded that coupling securin degradation with changes in Cdk1 and Cdc14 activities helps coordinate the initiation of sister chromatid separation with changes in spindle dynamics.

Tsukahara et al. (2010) isolated a fission yeast cyclin B (123836) mutant defective specifically in chromosome biorientation. Accordingly, Tsukahara et al. (2010) identified Cdk1-cyclin B-dependent phosphorylation of survivin. Preventing survivin phosphorylation impaired centromere chromosomal passenger complex (CPC) targeting as well as chromosome biorientation, whereas phosphomimetic survivin suppressed the biorientation defect in the cyclin B mutant. Survivin phosphorylation promoted direct binding with shugoshin (see 609168), which Tsukahara et al. (2010) defined as a conserved centromeric adaptor of the CPC. In human cells, the phosphorylation of borealin (609977) has a comparable role. Tsukahara et al. (2010) concluded that this study resolved the conserved mechanisms of CPC targeting to centromeres, highlighting a key role of Cdk1-cyclin B in chromosome biorientation.

Cdc2 inactivation by Wee1b (WEE2; 614084)-mediated phosphorylation is necessary for arrest of the oocyte at G2-prophase. Oh et al. (2011) showed that reactivation of a Wee1B pathway triggers the decrease in Cdc2 activity during egg activation. When Wee1B is downregulated, oocytes fail to form a pronucleus in response to calcium signals. Calcium-calmodulin-dependent kinase II (CaMKII; see 114078) activates Wee1B, and CaMKII-driven exit from metaphase II is inhibited by Wee1B downregulation, demonstrating that exit from metaphase requires not only a proteolytic degradation of cyclin B but also the inhibitory phosphorylation of Cdc2 by Wee1B.

Harbauer et al. (2014) found that CDK1 stimulated assembly of the main mitochondrial entry gate, the translocase of the outer membrane (TOM), in mitosis. In an S. cerevisiae assay, Harbauer et al. (2014) found that the molecular mechanism involves phosphorylation of the cytosolic precursor of TOM6 (616168) by cyclin CLB3-activated CDK1, leading to enhanced import of TOM6 into mitochondria. TOM6 phosphorylation promoted assembly of the protein import channel TOM40 (608061) and import of fusion proteins, thus stimulating the respiratory activity of mitochondria in mitosis. Harbauer et al. (2014) concluded that TOM6 phosphorylation provides a direct means for regulating mitochondrial biogenesis and activity in a cell cycle-specific manner.

Using systematic reconstitution and analysis of vertebrate anaphase-promoting complex/cyclosomes (APC/Cs) under physiologic conditions, Fujimitsu et al. (2016) showed how CDK1 activates the APC/C through coordinated phosphorylation between Apc3 (116946) and Apc1 (608473). Phosphorylation of the loop domains by CDK1 in complex with the CDK regulatory subunit p9/Cks2 (116901) controlled loading of coactivator Cdc20 (603618) onto APC/C. A phosphomimetic mutation introduced into Apc1 allowed Cdc20 to increase APC/C activity in interphase. These results defined a theretofore unrecognized subunit-subunit communication over a distance and the functional consequences of CDK phosphorylation.

The mitotic oscillator, centered on the CDK1-anaphase-promoting complex/cyclosome (CDK1-APC/C) axis, spatiotemporally coordinates organelle remodeling in dividing cells. Al Jord et al. (2017) discovered that nondividing cells could also implement this mitotic clocklike regulatory circuit to orchestrate subcellular reorganization associated with differentiation. Al Jord et al. (2017) probed centriole amplification in differentiating mouse brain multiciliated cells. These postmitotic progenitors fine-tuned mitotic oscillator activity to drive the orderly progression of centriole production, maturation, and motile ciliation while avoiding the mitosis commitment threshold. Insufficient CDK1 activity hindered differentiation, whereas excessive activity accelerated differentiation yet drove postmitotic progenitors into mitosis. Thus, Al Jord et al. (2017) concluded that postmitotic cells can redeploy and calibrate the mitotic oscillator to uncouple cytoplasmic from nuclear dynamics for organelle remodeling associated with differentiation.

Saldivar et al. (2018) demonstrated that cells transactivate the mitotic gene network as they exit the S phase through a CDK1-directed FOXM1 (602341) phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR (601215) is activated by ETAA1 (613196) to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint.


Mapping

Spurr et al. (1987, 1988) studied a panel of somatic cell hybrids and determined that the human homolog of the CDK1 gene is located on chromosome 10. By in situ hybridization, Nazarenko et al. (1991) regionalized the CDK1 gene to chromosome 10q21.


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Contributors:
Ada Hamosh - updated : 11/20/2018
Ada Hamosh - updated : 02/08/2018
Ada Hamosh - updated : 09/01/2016
Ada Hamosh - updated : 01/13/2015
Ada Hamosh - updated : 7/8/2011
Ada Hamosh - updated : 8/12/2008
Ada Hamosh - updated : 5/8/2008
Ada Hamosh - updated : 2/25/2008
Ada Hamosh - updated : 10/15/2007
Patricia A. Hartz - updated : 12/4/2006
Ada Hamosh - updated : 1/26/2005
Patricia A. Hartz - updated : 5/11/2004
Ada Hamosh - updated : 10/28/2003
Ada Hamosh - updated : 5/29/2003
Stylianos E. Antonarakis - updated : 9/18/2002
Jennifer P. Macke - updated : 5/27/1998

Creation Date:
Victor A. McKusick : 8/31/1987

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