HGNC Approved Gene Symbol:CDK4
Cytogenetic location:12q14.1 Genomic coordinates(GRCh38) :12:57,747,727-57,752,310 (from NCBI)
Cyclin-dependent kinase-4 (CDK4) is a protein-serine kinase involved in the cell cycle. Human cell division is regulated primarily at the G1-to-S or the G2-to-M boundaries within the cell cycle. The sequential activation of cyclin-dependent kinases and their subsequent phosphorylation of critical substrates promote orderly progression through the cell cycle. The complexes formed by CDK4 and the D-type cyclins (e.g., D1,168461; D2,123833; D3,123834) are involved in the control of cell proliferation during the G1 phase. CDK4 is inhibited by p16, also known as cyclin-dependent kinase inhibitor-2 (CDKN2A;600160).
Hanks (1987) isolated the CDK4 gene by screening a HeLa cell cDNA library with probes designed to recognize clones encoding protein-serine kinases.Zuo et al. (1996) noted that the CDK4 protein comprises 303 amino acids.
Zuo et al. (1996) determined that the CDK4 gene contains 8 exons and spans 5 kb.
Demetrick et al. (1994) mapped the CDK4 gene to chromosome 12q13 by fluorescence in situ hybridization. CDK2 maps to the same band. By fluorescence in situ hybridization,Mitchell et al. (1995) mapped CDK4 to 12q14 and concluded that it is distal to GLI (165220) and CHOP (126337), which they placed at 12q13.3-q14.1; and proximal to MDM2 (164785), which they placed at 12q14.3-q15.
Harbour et al. (1999) presented evidence that phosphorylation of the C-terminal region of RB1 (614041) by CDK4/CDK6 (603368) initiated successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaced histone deacetylase from the pocket, blocking active transcriptional repression of E2F (189971) by RB. This facilitated a second interaction that led to phosphorylation of the pocket by CDK2 (116953) and disruption of pocket structure. These intramolecular interactions provided a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 was activated early in G1, blocking active repression by RB. Cyclin E (see123837) and CDK2 were activated near the end of G1.
Stepanova et al. (1996) found that CDC37 (605065) and HSP90 (see140571) associated preferentially with the fraction of CDK4 not bound to D-type cyclins. Pharmacologic inactivation of CDC37/HSP90 function led to reduced stability of CDK4.
Modiano et al. (2000) found that 5 of 16 healthy individuals expressed CDK4 mRNA, protein, and activity in unstimulated peripheral blood T cells and that these T cells proliferated directly in response to interleukin-2 (IL2;147680) in the absence of mitogens. In cells from these individuals, CDK4 expression and activity were resistant to protein kinase inhibitors, unlike stimulated cells from individuals lacking basal CDK4 expression. The phenotype of the T cells of these individuals was comparable to that observed in a human IL2-dependent T-cell line.Modiano et al. (2000) proposed that CDK4 activity may be a useful marker for cytokine responsiveness in T cells.
In primary epidermal cells,Lazarov et al. (2002) found that oncogenic RAS (190020) transiently decreased CDK4 expression in association with cell cycle arrest in the G1 phase. CDK4 coexpression circumvented RAS growth suppression and induced invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis was dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, RAS and CDK4 altered the composition of cyclin D and cyclin E complexes and promoted resistance to growth inhibition by INK4 (600160) cyclin-dependent kinase inhibitors. These data identified a new role for oncogenic RAS in CDK4 regulation and highlighted the functional importance of CDK4 suppression in preventing uncontrolled growth.
Matsuura et al. (2004) showed that SMAD3 (603109) is a major physiologic substrate of the G1 cyclin-dependent kinases CDK4 and CDK2. Except for the retinoblastoma protein family, SMAD3 was the only CDK4 substrate demonstrated to that time.Matsuura et al. (2004) mapped CDK4 and CDK2 phosphorylation sites to thr8, thr178, and ser212 in SMAD3. Mutation of the CDK phosphorylation sites increased Smad3 transcriptional activity, leading to higher expression of the CDK inhibitor p15 (600431). Mutation of the CDK phosphorylation sites of Smad3 also increased its ability to downregulate the expression of c-myc (190080). Using Smad3 knockout mouse embryonic fibroblasts and other epithelial cell lines,Matsuura et al. (2004) further showed that Smad3 inhibited cell cycle progression from G1 to S phase and that mutation of the CDK phosphorylation sites in Smad3 increased this ability. They concluded that CDK phosphorylation of SMAD3 inhibits its transcriptional activity and antiproliferative function.
Lee et al. (2014) reported that in mice, insulin activates Ccnd1 (168461)/Cdk4, which in turn increases Gcn5 (KAT2A;602301) acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen,Lee et al. (2014) identified a Cdk4 inhibitor that potently decreases Pgc1a (PPARGC1A;604517) acetylation. Insulin/Gsk3b (605004) signaling induces Ccnd1 protein stability by sequestering Ccnd1 in the nucleus. In parallel, dietary amino acids increase hepatic Ccnd1 mRNA transcripts. Activated Ccnd1/Cdk4 kinase phosphorylates and activates Gcn5, which then acetylates and inhibits Pgc1a activity on gluconeogenic genes. Loss of hepatic Ccnd1 results in increased gluconeogenesis and hyperglycemia. In diabetic models, Ccnd1/Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless, further activation of this kinase normalizes glycemia.Lee et al. (2014) concluded that insulin uses components of the cell cycle machinery in postmitotic cells to control glucose homeostasis independently of cell division.
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.
In a human cutaneous malignant melanoma (CMM3;609048) cell line,Wolfel et al. (1995) identified a mutation in the CDK4 gene (R24C;123829.0001). The same mutation was found in 1 additional melanoma among 28 melanomas analyzed.
Zuo et al. (1996) identified germline R24C mutations in affected members of 2 unrelated families with malignant melanoma.
Soufir et al. (1998) identified an R24H (123829.0002) mutation in a French family with malignant melanoma.
In a large Norwegian pedigree first reported byGrimstvedt (1969),Molven et al. (2005) identified the R24H mutation.Molven et al. (2005) stated that whereas approximately 20% of melanoma-prone families bear a mutation in the CDKN2A locus (600160), mutations in the CDK4 locus are much rarer, having been linked to the disease in only 6 families worldwide.
Zou et al. (2002) noted that Cdk4-null mice were viable, but exhibited diabetes mellitus due to degeneration of pancreatic beta cells, as well as growth retardation and infertility due to severe hypoplasia and dysfunction of the pituitary. Embryonic fibroblasts from Cdk4-null mice initially proliferated at normal rates, but they displayed a 4- to 5-hour delay in reentry into the cell cycle following quiescence.Zou et al. (2002) found that Cdk4 was required for Ras-mediated transformation, and Cdk4 disruption led to senescence that was independent of Arf (600160) or p53 (191170). Senescence was associated with increased Cdkn1a (116899) stability.
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 a cutaneous malignant melanoma-3 (CMM3;609048) cell line,Wolfel et al. (1995) identified an arg24-to-cys (R24C) mutation in the CDK4 gene. The mutated CDK4 allele was present in autologous cultured melanoma cells and metastatic tissue, but not in the patient's lymphocytes, indicating a somatic mutation. The R24C mutation was part of the CDK4 peptide recognized by cytolytic T lymphocytes and prevented binding of the CDK4 inhibitor p16(INK4A) (600160), but not of p21 (300237) or of p27 (KIP1;600778). The results suggested that mutation of CDK4 disrupted the cell cycle regulation exerted by the tumor suppressor p16, resulting in a genetic predisposition to melanoma. The same mutation, typical of a UV lesion, was found in 1 additional melanoma among 28 melanomas analyzed. The mutated CDK4 protein had been identified as a tumor-specific antigen recognized by HLA-A 2.1 restricted autologous cytolytic T lymphocytes in the human melanoma tissue.Wolfel et al. (1995) suggested that the tumor-specific antigen defined by the R24C mutation in this patient became a target of tumor rejection responses because the patient had remained free of detectable disease for 7 years.
Zuo et al. (1996) identified the R24C mutation as a germline mutation in 2 families with malignant melanoma. The mutation was detected in 11 of 11 melanoma patients, 2 of 17 unaffected individuals, and in none of 5 spouses. Although the R24C mutation has a specific effect on the CDK4 p16(INK4A)-binding domain, it has no effect on the ability of CDK4 to bind cyclin D and form a functional kinase.Zuo et al. (1996) concluded that the germline R24C mutation generates a dominant oncogene that is resistant to normal physiologic inhibition by p16(INK4A). They noted that the only previous example of a dominant oncogene transmitted in the human germline was the RET (164761) gene that gives rise to MEN2A (171400), MEN2B (162300), and medullary thyroid carcinoma (171400).
In 1 of 48 (2%) French families with cutaneous malignant melanoma (CMM3;609048),Soufir et al. (1998) identified an arg24-to-his (R24H) germline mutation in the CDK4 gene.
In a large Norwegian pedigree with multiple atypical nevi and malignant melanomas first reported byGrimstvedt (1969),Molven et al. (2005) identified the R24H mutation. Six generations and more than 100 family members were traced, and 20 cases of melanoma were verified. One of the family members had ocular melanoma, but a CDK4 mutation could not be detected in archival tissue samples from this subject. The authors concluded that ocular melanoma in this family was sporadic, suggesting an etiology different from that of the skin tumors.Molven et al. (2005) cited unpublished data on an Australian and an English melanoma family, both with the R24H mutation. Although the CDK4 mutation in the Norwegian family was identical to that in melanoma families in France, Australia, and England, haplotype analysis using microsatellite markers flanking the CDK4 gene and SNPs within the gene did not support the possibility of a common founder, but rather indicated at least 2 independent mutational events.Molven et al. (2005) noted that all CDK4 melanoma families reported to that date had a substitution of amino acid 24, which may be the result of selection pressure. They suggested that the CG dinucleotide of codon 24 may represent a mutation hotspot in the CDK4 gene.
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. Note: Erratum: Nature 630: E14, 2024. [PubMed:37407814,images,related citations] [Full Text]
Demetrick, D. J., Zhang, H., Beach, D. H.Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes. Cytogenet. Cell Genet. 66: 72-74, 1994. [PubMed:8275715,related citations] [Full Text]
Grimstvedt, M.[Familial incidence of malignant melanoma]. Tidsskr. Nor. Laegeforen. 89: 1900-1902, 1969. [PubMed:5377176,related citations]
Hanks, S. K.Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family. Proc. Nat. Acad. Sci. 84: 388-392, 1987. [PubMed:2948189,related citations] [Full Text]
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,related citations] [Full Text]
Lazarov, M., Kubo, Y., Cai, T., Dajee, M., Tarutani, M., Lin, Q., Fang, M., Tao, S., Green, C. L., Khavari, P. A.CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nature Med. 8: 1105-1114, 2002. [PubMed:12357246,related citations] [Full Text]
Lee, Y., Dominy, J. E., Choi, Y. J., Jurczak, M., Tolliday, N., Camporez, J. P., Chim, H., Lim, J.-H., Ruan, H.-B., Yang, X., Vazquez, F., Sicinski, P., Shulman, G. I., Puigserver, P.Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature 510: 547-551, 2014. [PubMed:24870244,images,related citations] [Full Text]
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,related citations] [Full Text]
Matsuura, I., Denissova, N. G., Wang, G., He, D., Long, J., Liu, F.Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430: 226-231, 2004. [PubMed:15241418,related citations] [Full Text]
Mitchell, E. L. D., White, G. R. M., Santibanez-Koref, M. F., Varley, J. M., Heighway, J.Mapping of gene loci in the q13-q15 region of chromosome 12. Chromosome Res. 3: 261-262, 1995. [PubMed:7606365,related citations] [Full Text]
Modiano, J. F., Mayor, J., Ball, C., Fuentes, M. K., Linthicum, D. S.CDK4 expression and activity are required for cytokine responsiveness in T cells. J. Immun. 165: 6693-6702, 2000. [PubMed:11120786,related citations] [Full Text]
Molven, A., Grimstvedt, M. B., Steine, S. J., Harland, M., Avril, M.-F., Hayward, N. K., Akslen, L. A.A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation. Genes Chromosomes Cancer 44: 10-18, 2005. [PubMed:15880589,related citations] [Full Text]
Soufir, N., Avril, M. F., Chompret, A., Demenais, F., Bombled, J., Spatz, A., Stoppa-Lyonnet, D., Benard, J., Bressac-de Paillerets, B.Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France: the French Familial Melanoma Study Group. Hum. Molec. Genet. 7: 209-216, 1998. Note: Erratum: Hum. Molec. Genet. 7: 941 only, 1998. [PubMed:9425228,related citations] [Full Text]
Stepanova, L., Leng, X., Parker, S. B., Harper, J. W.Mammalian p50(Cdc37) is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10: 1491-1502, 1996. [PubMed:8666233,related citations] [Full Text]
Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., Klehmann-Hieb, E., De Plaen, E., Hankeln, T., Meyer zum Buschenfelde, K.-H., Beach, D.A p16(INK4a)-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269: 1281-1284, 1995. [PubMed:7652577,related citations] [Full Text]
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,images,related citations] [Full Text]
Zou, X., Ray, D., Aziyu, A., Christov, K., Boiko, A. D., Gudkov, A. V., Kiyokawa, H.Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence. Genes Dev. 16: 2923-2934, 2002. [PubMed:12435633,images,related citations] [Full Text]
Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., Walker, G. J., Hayward, N., Dracopoli, N. C.Germline mutations in the p16(INK4a) binding domain of CDK4 in familial melanoma. Nature Genet. 12: 97-99, 1996. [PubMed:8528263,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: CDK4
Cytogenetic location: 12q14.1 Genomic coordinates(GRCh38) : 12:57,747,727-57,752,310(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 12q14.1 | {Melanoma, cutaneous malignant, 3} | 609048 | Autosomal dominant | 3 |
Cyclin-dependent kinase-4 (CDK4) is a protein-serine kinase involved in the cell cycle. Human cell division is regulated primarily at the G1-to-S or the G2-to-M boundaries within the cell cycle. The sequential activation of cyclin-dependent kinases and their subsequent phosphorylation of critical substrates promote orderly progression through the cell cycle. The complexes formed by CDK4 and the D-type cyclins (e.g., D1, 168461; D2, 123833; D3, 123834) are involved in the control of cell proliferation during the G1 phase. CDK4 is inhibited by p16, also known as cyclin-dependent kinase inhibitor-2 (CDKN2A; 600160).
Hanks (1987) isolated the CDK4 gene by screening a HeLa cell cDNA library with probes designed to recognize clones encoding protein-serine kinases. Zuo et al. (1996) noted that the CDK4 protein comprises 303 amino acids.
Zuo et al. (1996) determined that the CDK4 gene contains 8 exons and spans 5 kb.
Demetrick et al. (1994) mapped the CDK4 gene to chromosome 12q13 by fluorescence in situ hybridization. CDK2 maps to the same band. By fluorescence in situ hybridization, Mitchell et al. (1995) mapped CDK4 to 12q14 and concluded that it is distal to GLI (165220) and CHOP (126337), which they placed at 12q13.3-q14.1; and proximal to MDM2 (164785), which they placed at 12q14.3-q15.
Harbour et al. (1999) presented evidence that phosphorylation of the C-terminal region of RB1 (614041) by CDK4/CDK6 (603368) initiated successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaced histone deacetylase from the pocket, blocking active transcriptional repression of E2F (189971) by RB. This facilitated a second interaction that led to phosphorylation of the pocket by CDK2 (116953) and disruption of pocket structure. These intramolecular interactions provided a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 was activated early in G1, blocking active repression by RB. Cyclin E (see 123837) and CDK2 were activated near the end of G1.
Stepanova et al. (1996) found that CDC37 (605065) and HSP90 (see 140571) associated preferentially with the fraction of CDK4 not bound to D-type cyclins. Pharmacologic inactivation of CDC37/HSP90 function led to reduced stability of CDK4.
Modiano et al. (2000) found that 5 of 16 healthy individuals expressed CDK4 mRNA, protein, and activity in unstimulated peripheral blood T cells and that these T cells proliferated directly in response to interleukin-2 (IL2; 147680) in the absence of mitogens. In cells from these individuals, CDK4 expression and activity were resistant to protein kinase inhibitors, unlike stimulated cells from individuals lacking basal CDK4 expression. The phenotype of the T cells of these individuals was comparable to that observed in a human IL2-dependent T-cell line. Modiano et al. (2000) proposed that CDK4 activity may be a useful marker for cytokine responsiveness in T cells.
In primary epidermal cells, Lazarov et al. (2002) found that oncogenic RAS (190020) transiently decreased CDK4 expression in association with cell cycle arrest in the G1 phase. CDK4 coexpression circumvented RAS growth suppression and induced invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis was dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, RAS and CDK4 altered the composition of cyclin D and cyclin E complexes and promoted resistance to growth inhibition by INK4 (600160) cyclin-dependent kinase inhibitors. These data identified a new role for oncogenic RAS in CDK4 regulation and highlighted the functional importance of CDK4 suppression in preventing uncontrolled growth.
Matsuura et al. (2004) showed that SMAD3 (603109) is a major physiologic substrate of the G1 cyclin-dependent kinases CDK4 and CDK2. Except for the retinoblastoma protein family, SMAD3 was the only CDK4 substrate demonstrated to that time. Matsuura et al. (2004) mapped CDK4 and CDK2 phosphorylation sites to thr8, thr178, and ser212 in SMAD3. Mutation of the CDK phosphorylation sites increased Smad3 transcriptional activity, leading to higher expression of the CDK inhibitor p15 (600431). Mutation of the CDK phosphorylation sites of Smad3 also increased its ability to downregulate the expression of c-myc (190080). Using Smad3 knockout mouse embryonic fibroblasts and other epithelial cell lines, Matsuura et al. (2004) further showed that Smad3 inhibited cell cycle progression from G1 to S phase and that mutation of the CDK phosphorylation sites in Smad3 increased this ability. They concluded that CDK phosphorylation of SMAD3 inhibits its transcriptional activity and antiproliferative function.
Lee et al. (2014) reported that in mice, insulin activates Ccnd1 (168461)/Cdk4, which in turn increases Gcn5 (KAT2A; 602301) acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, Lee et al. (2014) identified a Cdk4 inhibitor that potently decreases Pgc1a (PPARGC1A; 604517) acetylation. Insulin/Gsk3b (605004) signaling induces Ccnd1 protein stability by sequestering Ccnd1 in the nucleus. In parallel, dietary amino acids increase hepatic Ccnd1 mRNA transcripts. Activated Ccnd1/Cdk4 kinase phosphorylates and activates Gcn5, which then acetylates and inhibits Pgc1a activity on gluconeogenic genes. Loss of hepatic Ccnd1 results in increased gluconeogenesis and hyperglycemia. In diabetic models, Ccnd1/Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless, further activation of this kinase normalizes glycemia. Lee et al. (2014) concluded that insulin uses components of the cell cycle machinery in postmitotic cells to control glucose homeostasis independently of cell division.
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.
In a human cutaneous malignant melanoma (CMM3; 609048) cell line, Wolfel et al. (1995) identified a mutation in the CDK4 gene (R24C; 123829.0001). The same mutation was found in 1 additional melanoma among 28 melanomas analyzed.
Zuo et al. (1996) identified germline R24C mutations in affected members of 2 unrelated families with malignant melanoma.
Soufir et al. (1998) identified an R24H (123829.0002) mutation in a French family with malignant melanoma.
In a large Norwegian pedigree first reported by Grimstvedt (1969), Molven et al. (2005) identified the R24H mutation. Molven et al. (2005) stated that whereas approximately 20% of melanoma-prone families bear a mutation in the CDKN2A locus (600160), mutations in the CDK4 locus are much rarer, having been linked to the disease in only 6 families worldwide.
Zou et al. (2002) noted that Cdk4-null mice were viable, but exhibited diabetes mellitus due to degeneration of pancreatic beta cells, as well as growth retardation and infertility due to severe hypoplasia and dysfunction of the pituitary. Embryonic fibroblasts from Cdk4-null mice initially proliferated at normal rates, but they displayed a 4- to 5-hour delay in reentry into the cell cycle following quiescence. Zou et al. (2002) found that Cdk4 was required for Ras-mediated transformation, and Cdk4 disruption led to senescence that was independent of Arf (600160) or p53 (191170). Senescence was associated with increased Cdkn1a (116899) stability.
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 a cutaneous malignant melanoma-3 (CMM3; 609048) cell line, Wolfel et al. (1995) identified an arg24-to-cys (R24C) mutation in the CDK4 gene. The mutated CDK4 allele was present in autologous cultured melanoma cells and metastatic tissue, but not in the patient's lymphocytes, indicating a somatic mutation. The R24C mutation was part of the CDK4 peptide recognized by cytolytic T lymphocytes and prevented binding of the CDK4 inhibitor p16(INK4A) (600160), but not of p21 (300237) or of p27 (KIP1; 600778). The results suggested that mutation of CDK4 disrupted the cell cycle regulation exerted by the tumor suppressor p16, resulting in a genetic predisposition to melanoma. The same mutation, typical of a UV lesion, was found in 1 additional melanoma among 28 melanomas analyzed. The mutated CDK4 protein had been identified as a tumor-specific antigen recognized by HLA-A 2.1 restricted autologous cytolytic T lymphocytes in the human melanoma tissue. Wolfel et al. (1995) suggested that the tumor-specific antigen defined by the R24C mutation in this patient became a target of tumor rejection responses because the patient had remained free of detectable disease for 7 years.
Zuo et al. (1996) identified the R24C mutation as a germline mutation in 2 families with malignant melanoma. The mutation was detected in 11 of 11 melanoma patients, 2 of 17 unaffected individuals, and in none of 5 spouses. Although the R24C mutation has a specific effect on the CDK4 p16(INK4A)-binding domain, it has no effect on the ability of CDK4 to bind cyclin D and form a functional kinase. Zuo et al. (1996) concluded that the germline R24C mutation generates a dominant oncogene that is resistant to normal physiologic inhibition by p16(INK4A). They noted that the only previous example of a dominant oncogene transmitted in the human germline was the RET (164761) gene that gives rise to MEN2A (171400), MEN2B (162300), and medullary thyroid carcinoma (171400).
In 1 of 48 (2%) French families with cutaneous malignant melanoma (CMM3; 609048), Soufir et al. (1998) identified an arg24-to-his (R24H) germline mutation in the CDK4 gene.
In a large Norwegian pedigree with multiple atypical nevi and malignant melanomas first reported by Grimstvedt (1969), Molven et al. (2005) identified the R24H mutation. Six generations and more than 100 family members were traced, and 20 cases of melanoma were verified. One of the family members had ocular melanoma, but a CDK4 mutation could not be detected in archival tissue samples from this subject. The authors concluded that ocular melanoma in this family was sporadic, suggesting an etiology different from that of the skin tumors. Molven et al. (2005) cited unpublished data on an Australian and an English melanoma family, both with the R24H mutation. Although the CDK4 mutation in the Norwegian family was identical to that in melanoma families in France, Australia, and England, haplotype analysis using microsatellite markers flanking the CDK4 gene and SNPs within the gene did not support the possibility of a common founder, but rather indicated at least 2 independent mutational events. Molven et al. (2005) noted that all CDK4 melanoma families reported to that date had a substitution of amino acid 24, which may be the result of selection pressure. They suggested that the CG dinucleotide of codon 24 may represent a mutation hotspot in the CDK4 gene.
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