Alternative titles; symbols
HGNC Approved Gene Symbol: CDKN2D
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:10,566,460-10,568,979 (from NCBI)
Cyclins are important in regulating the cell cycle through their formation of enzymatic complexes with various cyclin-dependent kinases. The D type cyclins complex with CDK4 (123829) and CDK6 (603368) to govern progression through the G1 phase of the cell cycle and later are involved with inactivating phosphorylation of the RB1 protein (614041), which results in release of RB1-associated transcription factors that are needed for entry into S phase (Okuda et al., 1995). The activity of the cyclin D-dependent kinases is, in part, controlled by inhibitors such as the INK4 family, which includes INK4a (CDKN2A; 600160), 4b (CDKN2B; 600431), 4c (CDKN2C; 603369), and 4d (CDKN2D). INK4a has been shown to act by competing with CDK4 and CDK6 and functions as a tumor suppressor in a variety of cancers.
The INK4d protein was first identified in a yeast 2-hybrid system screened for CDK4 binding proteins (Hirai et al., 1995).
Okuda et al. (1995) described the cloning of the human INK4d gene (CDKN2D). The predicted 166-amino acid protein is 86% identical to the mouse protein and about 45% identical to other human INK4 family members. Northern blot analysis showed that the 1.4-kb transcript is ubiquitously expressed, with the highest levels in tissues with the most rapidly dividing cells. Lowest expression occurred at mid-G1 phase and was highest during S phase.
The mouse INK4d protein interacts with Cdk6. In fibroblasts and macrophages it is rapidly induced at the G1-to-S transition. Overexpression of INK4d caused NIH 3T3 cells to arrest in G1 phase and inhibited cyclin D1-CDK4 kinase activity (Hirai et al., 1995).
Matsuzaki et al. (2002) characterized the CDKN2D promoter region using sequence analysis and truncated 5-prime flanking regions in luciferase reporter assays. They identified several SP1 (189906) and AP2 (107580) sites within an active promoter region and found that mutation of the second SP1 site reduced promoter activity. There was no TATA box.
Okuda et al. (1995) obtained a P1-phage genomic clone including the gene and mapped it by fluorescence in situ hybridization to 19p13.
Zindy et al. (1999) generated mice with targeted deletions of both the Ink4d and Kip1 genes. They found that terminally differentiated, postmitotic neurons in these mice reentered the cell cycle, divided, and underwent apoptosis. Zindy et al. (1999) noted that when either Ink4d or Kip1 alone are deleted, the postmitotic state is maintained, suggesting a redundant role for these genes in mature neurons.
Zindy et al. (2000) generated Ink4d-null mice by targeted gene disruption. These animals developed into adulthood and had normal life spans. Males exhibited marked testicular atrophy associated with increased apoptosis of germ cells, although they remained fertile. Ink4d-null mice did not spontaneously develop tumors, and they showed normal sensitivity to ionizing radiation and carcinogens. Zindy et al. (2000) concluded that Ink4d is not a tumor suppressor but is involved in spermatogenesis.
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 Ink4d alone was associated with elevated levels of follicle-stimulating hormone. Loss of Ink4c or Ink4d, either singly or in combination, had no effect on female reproductive function.
In the organ of Corti, sensory hair cells and supporting cells become postmitotic during embryogenesis and remain quiescent for the life of the animal. When lost as a result of environmental insult or genetic abnormality, hair cells do not regenerate, and this loss is a common cause of deafness in humans. Chen et al. (2003) reported that targeted deletion of Ink4d alone was sufficient to disrupt the maintenance of the postmitotic state of sensory hair cells in postnatal mice. In Ink4d -/- animals, hair cells aberrantly reentered the cell cycle and subsequently underwent apoptosis, resulting in progressive hearing loss.
Chen, P., Zindy, F., Abdala, C., Liu, F., Li, X., Roussel, M. F., Segil, N. Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nature Cell Biol. 5: 422-426, 2003. [PubMed: 12717441] [Full Text: https://doi.org/10.1038/ncb976]
Hirai, H., Roussel, M. F., Kato, J.-Y., Ashmun, R. A., Sherr, C. J. Novel INK4 proteins, p19 and p18, are specific inhibitors of cyclin D-dependent kinases CDK4 and CDK6. Molec. Cell. Biol. 15: 2672-2681, 1995. [PubMed: 7739547] [Full Text: https://doi.org/10.1128/MCB.15.5.2672]
Matsuzaki, Y., Miyazawa, K., Yokota, T., Hitomi, T., Yamagishi, H., Sakai, T. Molecular cloning and characterization of the human p19(INK4d) gene promoter. FEBS Lett. 517: 272-276, 2002. [PubMed: 12062451] [Full Text: https://doi.org/10.1016/s0014-5793(02)02647-9]
Okuda, T., Hirai, H., Valentine, V. A., Shurtleff, S. A., Kidd, V. J., Lahti, J. M., Sherr, C. J., Downing, J. R. Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases. Genomics 29: 623-630, 1995. [PubMed: 8575754] [Full Text: https://doi.org/10.1006/geno.1995.9957]
Zindy, F., Cunningham, J. J., Sherr, C. J., Jogal, S., Smeyne, R. J., Roussel, M. F. Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases. Proc. Nat. Acad. Sci. 96: 13462-13467, 1999. [PubMed: 10557343] [Full Text: https://doi.org/10.1073/pnas.96.23.13462]
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., van Deursen, J., Grosveld, G., Sherr, C. J., Roussel, M. F. INK4d-deficient mice are fertile despite testicular atrophy. Molec. Cell. Biol. 20: 372-378, 2000. [PubMed: 10594039] [Full Text: https://doi.org/10.1128/MCB.20.1.372-378.2000]