CDKN2D explained

Cyclin-dependent kinase 4 inhibitor D is an enzyme that in humans is encoded by the CDKN2D gene.^{[1] [2]}

The protein encoded by this gene is a member of the INK4 family of cyclin-dependent kinase inhibitors. This protein has been shown to form a stable complex with CDK4 or CDK6, and prevent the activation of the CDK kinases, thus function as a cell growth regulator that controls cell cycle G1 progression. The abundance of the transcript of this gene was found to oscillate in a cell-cycle dependent manner with the lowest expression at mid G1 and a maximal expression during S phase. The negative regulation of the cell cycle involved in this protein was shown to participate in repressing neuronal proliferation, as well as spermatogenesis. The expression of this gene and its protein product (p19) is observed in neurons with neurofibrillary tangles (NFTs) and it is suggested as a marker for senescent neurons.^[3] Two alternatively spliced variants of this gene, which encode an identical protein, have been reported.^[2]

Note, this protein should not be confused with p19-ARF (mouse) or the human equivalent p14ARF, which are alternative products of the CDKN2A gene.

Further reading

• Hirai H, Roussel MF, Kato JY . Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. . Mol. Cell. Biol. . 15 . 5 . 2672–81 . 1995 . 7739547 . 10.1128/MCB.15.5.2672. 230497 . etal.
• Chan FK, Zhang J, Cheng L . Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. . Mol. Cell. Biol. . 15 . 5 . 2682–8 . 1995 . 7739548 . 10.1128/MCB.15.5.2682. 230498 . etal.
• Guan KL, Jenkins CW, Li Y . Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4. . Mol. Biol. Cell . 7 . 1 . 57–70 . 1996 . 8741839 . 10.1091/mbc.7.1.57. 278612 . etal.
• Schwaller J, Pabst T, Koeffler HP . Expression and regulation of G1 cell-cycle inhibitors (p16INK4A, p15INK4B, p18INK4C, p19INK4D) in human acute myeloid leukemia and normal myeloid cells. . Leukemia . 11 . 1 . 54–63 . 1997 . 9001419 . 10.1038/sj.leu.2400522 . etal. free .
• Russo AA, Tong L, Lee JO . Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. . Nature . 395 . 6699 . 237–43 . 1998 . 9751050 . 10.1038/26155 . 1998Natur.395..237R . 204997058 . etal.
• Brotherton DH, Dhanaraj V, Wick S . Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d. . Nature . 395 . 6699 . 244–50 . 1998 . 9751051 . 10.1038/26164 . 1998Natur.395..244B . 13337394 . etal.
• Baumgartner R, Fernandez-Catalan C, Winoto A . Structure of human cyclin-dependent kinase inhibitor p19INK4d: comparison to known ankyrin-repeat-containing structures and implications for the dysfunction of tumor suppressor p16INK4a. . Structure . 6 . 10 . 1279–90 . 1998 . 9782052 . 10.1016/S0969-2126(98)00128-2 . etal. free .
• Schreiber M, Muller WJ, Singh G, Graham FL . Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16INK4A, p18INK4C, p19INK4D, p21(WAF1/CIP1) and p27KIP1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity. . Oncogene . 18 . 9 . 1663–76 . 1999 . 10208428 . 10.1038/sj.onc.1202466 . free .
• Newton Bishop JA, Harland M, Bennett DC . Mutation testing in melanoma families: INK4A, CDK4 and INK4D. . Br. J. Cancer . 80 . 1–2 . 295–300 . 1999 . 10390011 . 10.1038/sj.bjc.6690354 . 2363010 . etal.
• Zindy F, Cunningham JJ, Sherr CJ . Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases. . Proc. Natl. Acad. Sci. U.S.A. . 96 . 23 . 13462–7 . 1999 . 10557343 . 10.1073/pnas.96.23.13462 . 23970 . 1999PNAS...9613462Z . etal. free .
• Thullberg M, Bartkova J, Khan S . Distinct versus redundant properties among members of the INK4 family of cyclin-dependent kinase inhibitors. . FEBS Lett. . 470 . 2 . 161–6 . 2000 . 10734227 . 10.1016/S0014-5793(00)01307-7 . 45439595 . etal. free .
• Bartkova J, Thullberg M, Rajpert-De Meyts E . Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis. . Oncogene . 19 . 36 . 4146–50 . 2000 . 10962575 . 10.1038/sj.onc.1203769 . etal. free .
• Fink JR, LeBien TW . Novel expression of cyclin-dependent kinase inhibitors in human B-cell precursors. . Exp. Hematol. . 29 . 4 . 490–8 . 2001 . 11301189 . 10.1016/S0301-472X(01)00619-1 . free .
• Zeeb M, Rösner H, Zeslawski W . Protein folding and stability of human CDK inhibitor p19(INK4d). . J. Mol. Biol. . 315 . 3 . 447–57 . 2002 . 11786024 . 10.1006/jmbi.2001.5242 . etal.
• Matsuzaki Y, Miyazawa K, Yokota T . Molecular cloning and characterization of the human p19(INK4d) gene promoter. . FEBS Lett. . 517 . 1–3 . 272–6 . 2002 . 12062451 . 10.1016/S0014-5793(02)02647-9 . 82054693 . etal. free .
• Arcellana-Panlilio MY, Egeler RM, Ujack E . Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors. . Genes Chromosomes Cancer . 35 . 2 . 176–81 . 2002 . 12203782 . 10.1002/gcc.10108 . 27477191 . etal.
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• Gevaert K, Goethals M, Martens L . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. . Nat. Biotechnol. . 21 . 5 . 566–9 . 2004 . 12665801 . 10.1038/nbt810 . 23783563 . etal.
• Komata T, Kanzawa T, Takeuchi H . Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells. . Br. J. Cancer . 88 . 8 . 1277–80 . 2004 . 12698196 . 10.1038/sj.bjc.6600862 . 2747579 . etal.

Notes and References

1. Okuda T, Hirai H, Valentine VA, Shurtleff SA, Kidd VJ, Lahti JM, Sherr CJ, Downing JR . Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases . Genomics . 29 . 3 . 623–30 . Mar 1996 . 8575754 . 10.1006/geno.1995.9957 .
2. Web site: Entrez Gene: CDKN2D cyclin-dependent kinase inhibitor 2D (p19, inhibits CDK4).
3. Dehkordi . Shiva Kazempour . Walker . Jamie . Sah . Eric . Bennett . Emma . Atrian . Farzaneh . Frost . Bess . Woost . Benjamin . Bennett . Rachel E. . Orr . Timothy C. . Zhou . Yingyue . Andhey . Prabhakar S. . Colonna . Marco . Sudmant . Peter H. . Xu . Peng . Wang . Minghui . Zhang . Bin . Zare . Habil . Orr . Miranda E. . Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology . Nature Aging . December 2021 . 1 . 12 . 1107–1116 . 10.1038/s43587-021-00142-3 . 35531351 . 9075501 . 245059153 .