Alternative titles; symbols
HGNC Approved Gene Symbol: CDKN2C
Cytogenetic location: 1p32.3 Genomic coordinates (GRCh38) : 1:50,960,745-50,974,634 (from NCBI)
Cyclin-dependent kinase inhibitors (CKIs) are a group of low molecular weight proteins that associate with cyclin-CDK complexes or CDKs alone and inhibit their activity. Members of the INK4 family of CKIs, which includes CDKN2C, specifically bind and inhibit CDK4 (123829) and CDK6 (603368), thereby preventing cyclin D-dependent phosphorylation of RB1 (614041). See INK4D (600947).
By using a yeast 2-hybrid screen to search for CDK6-interacting proteins, Guan et al. (1994) isolated a partial cDNA encoding a protein that they designated p18 based on its molecular mass of 18 kD. They used the partial cDNA to screen a HeLa cell library and recovered additional cDNAs corresponding to the entire p18 coding region. Sequence analysis revealed that the predicted 168-amino acid p18 protein shares 38% and 42% sequence identity with p16/INK4A (600160) and p14/INK4B (600431), respectively. Like p14 and p16, p18 contains an ankyrin repeat domain. Using Northern blot analysis, Guan et al. (1994) found that p18 is expressed as multiple transcripts in various human tissues, with the strongest expression in skeletal muscle.
Guan et al. (1994) showed that, both in vivo and in vitro, p18 interacted strongly with CDK6 and weakly with CDK4, but not with the other CDKs tested. Recombinant p18 inhibited the kinase activity of cyclin D-CDK6 in vitro. Ectopic expression of either p16 or p18 suppressed the growth of human cells in a manner that appears to correlate with the presence of a wildtype RB1 function.
Blais et al. (1998) determined that the p18, or INK4C, gene contains 3 exons and spans more than 7.5 kb.
By fluorescence in situ hybridization, Guan et al. (1994) mapped the p18 gene to 1p32, a chromosomal region associated with abnormalities in a variety of human tumors.
Lapointe et al. (1996) identified a single amino acid substitution (ala72 to pro; A72P) in BT-20 human breast cancer cells that abrogated the ability of p18 to interact with CDK6 and to suppress cell growth. These authors suggested that p18 inactivation by point mutations may contribute to deregulated growth control in certain cell lines and/or tumors. Blais et al. (1998) found this p18 variant in 3 of 35 breast tumors examined, and suggested that it may be a polymorphism.
Zindy et al. (2001) determined that both Ink4c and Ink4d were expressed in the seminiferous tubules of postnatal wildtype mice, being largely confined to postmitotic spermatocytes undergoing meiosis. Loss of either Ink4c or Ink4d alone was associated with male fertility, but double-knockout males were sterile. Spermatogonia did not differentiate properly and became apoptotic. Residual spermatozoa had reduced motility and decreased viability. Loss of Ink4c alone or in combination with loss of Ink4d was associated with impaired differentiation of Leydig cells and reduced testosterone levels, but there was no effect on the levels of luteinizing hormone produced by the anterior pituitary. Loss of Ink4c or Ink4d, either singly or in combination, had no effect on female reproductive function.
Bai et al. (2003) noted that targeted disruption of Ink4c in mice leads to spontaneous pituitary tumors and lymphomas later in life. Treatment of Inc4c null and heterozygous mice with a chemical carcinogen resulted in tumor development at an accelerated rate. Bai et al. (2003) concluded that, since the remaining wildtype allele of Ink4c was neither mutated nor silenced in tumors derived from heterozygotes, Ink4c is a haploinsufficient tumor suppressor in mice.
Using reconstituted mice with p18-deficient hematopoietic cells and in vivo evaluation of stem cell function, Yuan et al. (2004) found that p18 inhibited cell division in hematopoietic stem cells and early hematopoietic progenitor cells.
Nmyc (164840) promotes rapid cell division of granule neuron progenitors (GNPs) in mice, and its conditional loss during embryonic cerebellar development results in severe GNP deficiency, perturbs foliation, and leads to reduced cerebellar mass. Since Nmyc loss triggers precocious expression of Kip1 (CDKN1B; 600778) and Ink4c in the cerebellar primordium, Zindy et al. (2006) disrupted Kip1 and Ink4c in Nmyc-null cerebella and found that this partially rescued GNP cell proliferation and cerebellar foliation. They concluded that expression of NMYC and concomitant downregulation of INK4C and KIP1 contribute to the proper development of the cerebellum.
Bai, F., Pei, X.-H., Godfrey, V. L., Xiong, Y. Haploinsufficiency of p18(INK4c) sensitizes mice to carcinogen-induced tumorigenesis. Molec. Cell. Biol. 23: 1269-1277, 2003. [PubMed: 12556487] [Full Text: https://doi.org/10.1128/MCB.23.4.1269-1277.2003]
Blais, A., Labrie, Y., Pouliot, F., Lachance, Y., Labrie, C. Structure of the gene encoding the human cyclin-dependent kinase inhibitor p18 and mutational analysis in breast cancer. Biochem. Biophys. Res. Commun. 247: 146-153, 1998. [PubMed: 9636670] [Full Text: https://doi.org/10.1006/bbrc.1998.8497]
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]
Lapointe, J., Lachance, Y., Labrie, Y., Labrie, C. A p18 mutant defective in CDK6 binding in human breast cancer cells. Cancer Res. 56: 4586-4589, 1996. [PubMed: 8840966]
Yuan, Y., Shen, H., Franklin, D. S., Scadden, D. T., Cheng, T. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18(INK4C). Nature Cell Biol. 6: 436-442, 2004. [PubMed: 15122268] [Full Text: https://doi.org/10.1038/ncb1126]
Zindy, F., den Besten, W., Chen, B., Rehg, J. E., Latres, E., Barbacid, M., Pollard, J. W., Sherr, C. J., Cohen, P. E., Roussel, M. F. Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18(Ink4c) and p19(Ink4d). Molec. Cell. Biol. 21: 3244-3255, 2001. [PubMed: 11287627] [Full Text: https://doi.org/10.1128/MCB.21.9.3244-3255.2001]
Zindy, F., Knoepfler, P. S., Xie, S., Sherr, C. J., Eisenman, R. N., Roussel, M. F. N-Myc and the cyclin-dependent kinase inhibitors p18(Ink4c) and p27(Kip1) coordinately regulate cerebellar development. Proc. Nat. Acad. Sci. 103: 11579-11583, 2006. [PubMed: 16864777] [Full Text: https://doi.org/10.1073/pnas.0604727103]