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Other entities represented in this entry:
HGNC Approved Gene Symbol: CDK6
Cytogenetic location: 7q21.2 Genomic coordinates (GRCh38): 7:92,604,921-92,836,573 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.2 | ?Microcephaly 12, primary, autosomal recessive | 616080 | Autosomal recessive | 3 |
The cyclin-dependent protein kinases (CDKs) regulate major cell cycle transitions in eukaryotic cells. By RT-PCR of HeLa cell mRNA with degenerate primers corresponding to conserved regions of CDC2 (116940), Meyerson et al. (1992) identified cDNAs encoding 7 novel human protein kinases. They designated 1 of these proteins PLSTIRE, following the accepted practice of naming cdc2-related kinases based on the amino acid sequence of the region corresponding to the conserved PSTAIRE motif of CDC2. The predicted 326-amino acid PLSTIRE protein shares 47% and 71% identity with CDC2 and PSK-J3 (CDK4; 123829). The in vitro transcription/translation product has an apparent molecular weight of 40 kD by SDS-PAGE. Northern blot analysis revealed that the PLSTIRE gene was expressed as 13-, 8.5-, and 6-kb mRNAs in several human tissues.
Hussain et al. (2013) found expression of Cdk6 in the neuroepithelium of the cerebral cortex of the developing mouse brain. Cdk6 immunostaining was prominent at the apical ventricular surface and in the basal progenitor cells. Within the cell, Cdk6 localized to the cytosol of neurons and showed prominent staining around either side of the nucleus.
Meyerson and Harlow (1994) demonstrated that PLSTIRE is associated with cyclins D1 (168461), D2 (123833), and D3 (123834) in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. PLSTIRE immunoprecipitated from human cells exhibited significant kinase activity, and was able to phosphorylate RB1 (614041). Based on these findings, they renamed the protein CDK6 (cyclin-dependent kinase 6). In primary T cells that were stimulated to enter the cell cycle, cellular CDK6 kinase activity first appeared in mid-G1, prior to the activation of any previously characterized CDK. Meyerson and Harlow (1994) suggested that CDK6, and the homologous CDK4, link growth factor stimulation with the onset of cell cycle progression.
Guan et al. (1994) proposed that CDK4 and CDK6 are physiologic RB1 kinases that are inhibited by the p14 (600431), p16 (600160), and p18 (603369) CDK inhibitors. This inhibition prevents the phosphorylation of RB1 and keeps RB1 in its active growth-suppressing state. See CDKN2D (600927).
Harbour et al. (1999) presented evidence that phosphorylation of the C-terminal region of RB by CDK4/CDK6 initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by RB. This facilitates a second interaction that leads to phosphorylation of the pocket by CDK2 and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 is activated early in G1, blocking active repression by RB. However, it is not until near the end of G1, when cyclin E (see 123837) is expressed and CDK2 is activated, that RB is prevented from binding and inactivating E2F (189971).
Veiga-Fernandes and Rocha (2003) showed that, in contrast to naive CD8 (see 186910) T cells in G0/G1 arrest, memory CD8 T cells in G0/G1 arrest have low expression of the cyclin-dependent kinase inhibitor p27(Kip1) (CDKN1B; 600778) and high CDK6 activity. They found that preactivated CDK6 is associated with cyclin D3 (CCND3) in the cytoplasm, facilitating the switch to S phase and the rapid division of memory cells. Veiga-Fernandes and Rocha (2003) concluded that naive T cells are in the classic state of G0/G1 arrest with low amounts of D cyclins and CDK6 and CDK2 (116953) activity but high levels of CDKN1B, whereas memory cells have high levels of CCND3 and CDK6 activity in a distinct G0/G1 state.
Using microarray analysis, Lena et al. (2012) found that microRNA-191 (MIR191; 615150) was significantly upregulated in normal human neonatal epidermal keratinocytes (HEKn) following development of senescence in culture. Bioinformatic analysis and reporter gene assays revealed functional MIR191 target sequences in the 3-prime UTRs of transcripts for CDK6 and the AT-rich binding protein SATB1 (602075). Western blot analysis confirmed that ectopic expression of MIR191 in HEKn cells caused downregulation of SATB1 and CDK6, concomitant with decreased cell proliferation and expression of senescence markers.
Hussain et al. (2013) found CDK6 in the cytoplasm and nuclei of nondividing HaCaT human keratinocytes. In dividing cells, cytoplasmic staining of CDK6 was reduced, and CDK6 localized with a centrosomal marker and accumulated at the centrosome during the mitotic cycle. Knockdown of CDK6 caused microtubule and centrosome aberrations and defects in the cell division cycle, manifest by supernumerary centrosomes, disorganized microtubules, abnormal mitotic spindles, and misshapen nuclei. CDK6-null cells also showed impaired cell motility and polarity.
Using human cancer cells and patient-derived xenografts in mice, Wang et al. (2017) showed that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of 2 key enzymes in the glycolytic pathway, 6-phosphofructokinase (see PFKP, 171840) and pyruvate kinase M2 (see 179050). This redirects the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumor cells reduced flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increased the levels of reactive oxygen species and caused apoptosis of tumor cells. The prosurvival function of cyclin D-associated kinase operates in tumors expressing high levels of cyclin D3-CDK6 complexes. Wang et al. (2017) proposed that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon inhibition of CDK4 and CDK6.
Zhang et al. (2018) showed that PDL1 (605402) protein abundance is regulated by cyclin D-CDK4 and the cullin 3 (603136)-SPOP (602650) E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 in vivo increases PDL1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of SPOP and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1 (603619). Loss-of-function mutations in SPOP compromise ubiquitination-mediated PDL1 degradation, leading to increased PDL1 levels and reduced numbers of tumor-infiltrating lymphocytes in mouse tumors and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD1 (600244) immunotherapy enhances tumor regression and markedly improves overall survival rates in mouse tumor models. Zhang et al. (2018) concluded that their study uncovered a novel molecular mechanism for regulating PDL1 protein stability by a cell cycle kinase and revealed the potential for using combination treatment with CDK4/6 inhibitors and PD1-PDL1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.
The restriction (R) point marks the point in the cell cycle when cells become independent of mitogen signaling and CDK2 activity becomes self-sustaining through a feedback loop between cyclin A2 (CCNA2; 123835)/CDK2 and RB1, leading to an irreversible commitment to proliferation. Cornwell et al. (2023) demonstrated that mitogen signaling maintained CDK2 activity in S and G2 phases of the cell cycle, and that, in the absence of mitogen signaling, some post-R-point cells exited the cell cycle and entered a G0-like state instead of irreversibly committing to proliferation. Further analysis indicated that mitosis and cell cycle exit were 2 mutually exclusive fates, and that competition between the 2 determined whether cells continued to proliferate or exited the cell cycle. As a result, the decision to proliferate was fully reversible, even when cells were in post-R state, because CDK2 activation and RB1 phosphorylation were reversible in all post-R cells after loss of mitogen signaling. CDK4/CDK6 promoted cyclin A2 synthesis in S/G2, and cyclin A2 stability was the primary contributor to cell cycle exit. Cells were dependent on mitogens and CDK4/CDK6 activity to maintain CDK2 activity and RB1 phosphorylation throughout the cell cycle. The R-point irreversibility phenomenon was observed in the absence of mitogens, because in most cells, the half-life of cyclin A2 was long enough to sustain CDK2 activity throughout G2/M to reach mitosis. The results implied that there is no single point when cells are irreversibly committed to proliferation that can be defined by a single molecular event, but rather that it is determined by the cell's proximity to mitosis, as well as the cyclin A2 level when mitogen signaling is lost.
By analysis of a somatic cell hybrid panel, Bullrich et al. (1995) mapped the CDK6 gene to 7p13-cen. However, radiation hybrid analysis and inclusion within a mapped clone place the CDK6 gene at 7q21-q22 (SGC34899).
In an infant diagnosed at the age of 3 weeks with acute lymphoblastic leukemia (ALL; 613065) after presenting with hepatosplenomegaly and marked leukocytosis, Raffini et al. (2002) found a 3-way rearrangement of the MLL (159555), AF4 (159557), and CDK6 genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. CDK6 is overexpressed or disrupted by translocation in many cancers, e.g., T cell lymphoblastic lymphoma (Chilosi et al., 1998), T cell ALL, natural killer/T cell nasal lymphoma (Lien et al., 2000), and glioblastoma multiforme (Costello et al., 1997). B cell splenic lymphomas with villous lymphocytes are characterized by t(2;7)(p12;q21) translocation juxtaposing CDK6 to the IGKC gene (147200). The patient of Raffini et al. (2002) had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript.
Primary Microcephaly 12, Autosomal Recessive
In affected members of a Pakistani family with autosomal recessive primary microcephaly-12 (MCPH12; 616080), Hussain et al. (2013) identified a homozygous missense mutation in the CDK6 gene (A197T; 603368.0001). The mutation, which was found by homozygosity mapping, candidate gene analysis, and whole-exome sequencing, segregated with the disorder in the family.
Associations Pending Confirmation
Because of sequence and functional similarities between CDK4 (123829), mutations in which cause familial melanoma (609048), and CDK6, Shennan et al. (2000) hypothesized that germline mutations in CDK6 might predispose to melanoma. They detected no CDK6 mutations, however, within the p16-binding domain in index cases from 60 melanoma-prone kindreds lacking germline mutations in the coding regions of either CDKN2A or within the entire CDK4 coding region. They concluded that germline mutations in CDK6 do not make a significant contribution to melanoma predisposition.
For a discussion of a possible association between variation in the CDK6 gene and stature, see STQTL11 (612223).
Malumbres et al. (2004) found that Cdk6-null mice were viable and developed normally, although hematopoiesis was slightly impaired. Embryos defective for Cdk4 and Cdk6 died during the late stages of embryonic development due to severe anemia. However, these embryos displayed normal organogenesis, and most cell types proliferated normally. In vitro, embryonic fibroblasts lacking Cdk4 and Cdk6 proliferated and became immortal upon serial passage. Quiescent Cdk4/Cdk6-null cells responded to serum stimulation and entered S phase with normal kinetics, although with lower efficiency. These results indicated that D-type cyclin-dependent kinases are not essential for cell cycle entry and suggested the existence of alternative mechanisms to initiate cell proliferation upon mitogenic stimulation.
In affected members of a large consanguineous Pakistani family with autosomal recessive primary microcephaly-12 (MCPH12; 616080), Hussain et al. (2013) identified a homozygous c.589G-A transition in exon 5 of the CDK6 gene, resulting in an ala197-to-thr (A197T) substitution at a highly conserved residue in vertebrates. The mutation, which was found by homozygosity mapping, candidate gene sequencing and whole-exome sequencing, segregated with the disorder in the family and was not present in the Exome Sequencing Project database, in 394 Pakistani controls, or in 380 German controls. During interphase, patient cells showed normal CDK6 localization, but during mitosis, mutant CDK6 did not localize at the centrosome, the mitotic spindles were disorganized with abnormal microtubule formation, and the nuclei were misshapen. Supernumerary centrosomes were also observed during mitosis. Patient cells showed a reduced growth rate and increased apoptosis compared to controls, as well as impaired motility and polarity. Hussain et al. (2013) postulated a loss-of-function effect of the mutation because the abnormalities observed in patient cells were similar to those observed in in vitro CDK6 knockdown studies.
Bullrich, F., MacLachlan, T. K., Sang, N., Druck, T., Veronese, M. L., Allen, S. L., Chiorazzi, N., Koff, A., Heubner, K., Croce, C. M., Giordano, A. Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27-Kip1, to regions involved in human cancer. Cancer Res. 55: 1199-1205, 1995. [PubMed: 7882308]
Chilosi, M., Doglioni, C., Yan, Z., Lestani, M., Menestrina, F., Sorio, C., Benedetti, A., Vinante, F., Pizzolo, G., Inghirami, G. Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia. Am. J. Path. 152: 209-217, 1998. [PubMed: 9422538]
Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D. Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal. Nature 619: 363-370, 2023. [PubMed: 37407814] [Full Text: https://doi.org/10.1038/s41586-023-06274-3]
Costello, J. F., Plass, C., Arap, W., Chapman, V. M., Held, W. A., Berger, M. S., Su Huang, H. J., Cavenee, W. K. Cyclin-dependent kinase 6 (cdk6) amplification in human gliomas identified using two-dimensional separation of genomic DNA. Cancer Res. 57: 1250-1254, 1997. [PubMed: 9102208]
Guan, K.-L., Jenkins, C. W., Li, Y., Nichols, M. A., Wu, X., O'Keefe, C. L., Matera, A. G., Xiong, Y. Growth suppression by p18, a p16(INK4/MTS1)- and p14(INK4B/MTS2)-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev. 8: 2939-2952, 1994. [PubMed: 8001816] [Full Text: https://doi.org/10.1101/gad.8.24.2939]
Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A., Dean, D. C. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98: 859-869, 1999. [PubMed: 10499802] [Full Text: https://doi.org/10.1016/s0092-8674(00)81519-6]
Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. Hum. Molec. Genet. 22: 5199-5214, 2013. [PubMed: 23918663] [Full Text: https://doi.org/10.1093/hmg/ddt374]
Lena, A. M., Mancini, M., Rivetti di Val Cervo, P. R., Saintigny, G., Mahe, C., Melino, G., Candi, E. MicroRNA-191 triggers keratinocytes senescence by SATB1 and CDK6 downregulation. Biochem. Biophys. Res. Commun. 423: 509-514, 2012. [PubMed: 22683624] [Full Text: https://doi.org/10.1016/j.bbrc.2012.05.153]
Lien, H.-C., Lin, C.-W., Huang, P.-H., Chang, M.-L., Hsu, S.-M. Expression of cyclin-dependent kinase 6 (cdk6) and frequent loss of CD44 in nasal-nasopharyngeal NK/T-cell lymphomas: comparison with CD56-negative peripheral T-cell lymphomas. Lab. Invest. 80: 893-900, 2000. [PubMed: 10879740] [Full Text: https://doi.org/10.1038/labinvest.3780093]
Malumbres, M., Sotillo, R., Santamaria, D., Galan, J., Cerezo, A., Ortega, S., Dubus, P., Barbacid, M. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118: 493-504, 2004. [PubMed: 15315761] [Full Text: https://doi.org/10.1016/j.cell.2004.08.002]
Meyerson, M., Enders, G. H., Wu, C.-L., Su, L.-K., Gorka, C., Nelson, C., Harlow, E., Tsai, L.-H. A family of human cdc2-related protein kinases. EMBO J. 11: 2909-2917, 1992. [PubMed: 1639063] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05360.x]
Meyerson, M., Harlow, E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Molec. Cell. Biol. 14: 2077-2086, 1994. [PubMed: 8114739] [Full Text: https://doi.org/10.1128/mcb.14.3.2077-2086.1994]
Raffini, L. J., Slater, D. J., Rappaport, E. F., Lo Nigro, L., Cheung, N.-K. V., Biegel, J. A., Nowell, P. C., Lange, B. J., Felix, C. A. Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6. Proc. Nat. Acad. Sci. 99: 4568-4573, 2002. [PubMed: 11930009] [Full Text: https://doi.org/10.1073/pnas.062066799]
Shennan, M. G., Badin, A.-C., Walsh, S., Summers, A., From, L., McKenzie, M., Goldstein, A. M., Tucker, M. A., Hogg, D., Lassam, N. Lack of germline CDK6 mutations in familial melanoma. Oncogene 19: 1849-1852, 2000. [PubMed: 10777219] [Full Text: https://doi.org/10.1038/sj.onc.1203507]
Veiga-Fernandes, H., Rocha, B. High expression of active CDK6 in the cytoplasm of CD8 memory cells favors rapid division. Nature Immun. 5: 31-37, 2003. [PubMed: 14647273] [Full Text: https://doi.org/10.1038/ni1015]
Wang, H., Nicolay, B. N., Chick, J. M., Gao, X., Geng, Y., Ren, H., Gao, H., Yang, G., Williams, J. A., Suski, J. M., Keibler, M. A., Sicinska, E., Gerdemann, U., Haining, W. N., Roberts, T. M., Polyak, K., Gygi, S. P., Dyson, N. J., Sicinski, P. The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 546: 426-430, 2017. [PubMed: 28607489] [Full Text: https://doi.org/10.1038/nature22797]
Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., Guo, J., Huang, Y.-H., Fan, C., Ren, S., Sun, Y., Freeman, G. J., Sicinski, P., Wei, W. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553: 91-95, 2018. Note: Erratum: Nature 571: E10, 2019. [PubMed: 29160310] [Full Text: https://doi.org/10.1038/nature25015]