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Gene Review

CDKN2D  -  cyclin-dependent kinase inhibitor 2D (p19,...

Homo sapiens

Synonyms: Cyclin-dependent kinase 4 inhibitor D, INK4D, p19, p19-INK4D, p19-INK4d
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Disease relevance of CDKN2D

  • Mutation testing in melanoma families: INK4A, CDK4 and INK4D [1].
  • Increased expression of unmethylated CDKN2D by 5-aza-2'-deoxycytidine in human lung cancer cells [2].
  • Interestingly, homozygous deletion of p16/p19 was observed in squamous metaplasia from bladder cancer patients (five of 11, 45%), showing that this change occurred in preneoplastic cells [3].
  • In this study, significantly higher levels of p19/nm23 occurred in primary neuroblastoma tumors from patients with advanced stages (III and IV) relative to tumors from patients with limited stages (I and II) of the disease [4].
  • Antibodies to HTLV-I core proteins p19 and p24 but not to HTLV-III proteins were detected in patient serum by Western blotting; patient cultured PBMC stained (7-11%) with antibodies to p19 and p24 [5].

High impact information on CDKN2D

  • The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19 INK4d protein has been determined at 1.9 A resolution [6].
  • High levels of p19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification [4].
  • The partial amino acid sequence obtained for p19 is identical to the sequence of the human nm23-H1 protein [4].
  • An antibody to the A subunit of erythrocyte nucleotide diphosphate kinase reacted exclusively with p19 [4].
  • In proliferating macrophages, p19 mRNA and protein are periodically expressed with a nadir in G1 phase and maximal synthesis during S phase, consistent with the possibility that INK4 proteins limit the activities of CDKs once cells exit G1 phase [7].

Biological context of CDKN2D

  • An initial precursor stage, intratubular germ cell neoplasia (IGCN), is characterized by triploidization and an upregulation of KIT, ALPP, CCDN2, and ZNF354A, and a downregulation of CDKN2D [8].
  • When phosphorylation reactions were performed with isolated nuclei (in vitro), three of these proteins were phosphorylated in a calcium and phospholipid dependent manner: p66, p36, and p19 P66 was phosphorylated in response to 1,25-(OH)2D3 and purified in a manner similar to that used for nuclear lamins [9].
  • Early acquisition of homozygous deletions of p16/p19 during squamous cell carcinogenesis and genetic mosaicism in bladder cancer [3].
  • Sequence conservation and conservation of synteny between human and Fugu predict one gene to be an INK4A or INK4B homologue and the other an INK4D homologue [10].
  • Therefore, p19 might complement the function of less stable INK4 inhibitors in cell cycle control under unfavorable conditions [11].

Anatomical context of CDKN2D


Associations of CDKN2D with chemical compounds

  • Treatment of cells with 5-aza-2'-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methyltransferase 1, induced a dose and duration dependent increased expression of both p16(INK4a) and p19(INK4d), the products of CDKN2A and CDKN2D, respectively [2].
  • Homotypic protein-protein disulfide bridges were found to originate from near the carboxy terminus of p19, from cysteine residues at amino acids 111 and 153 [13].
  • 5. Using specific radioimmunoassays, p19 and p15 were shown to band with HTLV on sucrose gradients [14].

Other interactions of CDKN2D

  • Alterations of the cyclin-dependent kinase inhibitor p19 (INK4D) is rare in hematopoietic malignancies [15].
  • In an attempt to identify another melanoma susceptibility gene, a member of the INK4 family, the p19 INK4D gene has been studied [1].
  • The expression of both the BIRC3 and CDKN2D genes was significantly higher in the early-stage group than in the advanced-stage group (P = 0.002 and 0.003, respectively), whereas the expression of the SMARCD3 gene was significantly reduced in the early-stage group (P = 0.02) [16].
  • The genes CTL2, KEAP1 and CDKN2D were screened but were negative for functional sequence variants [17].
  • IL-4 favored the induction of cytokines and of genes associated with cell growth arrest (GADD34, GAS-1, CIDE-A, INK4D, and BAX) and completely abolished the enhanced proliferation observed in the other 3 groups after activation [18].

Analytical, diagnostic and therapeutic context of CDKN2D

  • Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases [19].
  • Within this report, we report on the complete cloning, genomic exon/intron boundary delineation, linkage mapping and expressional characteristics of Xiphophorus CDKN2D [20].
  • In immunoblotting of cultured choriocarcinoma cells, anti-HTLV p19 detected a single polypeptide at mol.wt 28,000 from proteins separated by electrophoresis [12].
  • All of 11 MA-ELISA positive animals which were subjected to further testing were also positive in a competition assay for anti-HTLV p19 antibodies and in an anti-whole virion enzyme immunoassay [21].
  • In order to obtain a tool for the detection and identification of HTLV I in cell culture we have developed an antigen-capture ELISA, which is based on the use of rabbit hyperimmune serum on solid phase and mouse monoclonal antibodies against p19 and p24 as tracers [22].


  1. Mutation testing in melanoma families: INK4A, CDK4 and INK4D. Newton Bishop, J.A., Harland, M., Bennett, D.C., Bataille, V., Goldstein, A.M., Tucker, M.A., Ponder, B.A., Cuzick, J., Selby, P., Bishop, D.T. Br. J. Cancer (1999) [Pubmed]
  2. Increased expression of unmethylated CDKN2D by 5-aza-2'-deoxycytidine in human lung cancer cells. Zhu, W.G., Dai, Z., Ding, H., Srinivasan, K., Hall, J., Duan, W., Villalona-Calero, M.A., Plass, C., Otterson, G.A. Oncogene (2001) [Pubmed]
  3. Early acquisition of homozygous deletions of p16/p19 during squamous cell carcinogenesis and genetic mosaicism in bladder cancer. Tsutsumi, M., Tsai, Y.C., Gonzalgo, M.L., Nichols, P.W., Jones, P.A. Oncogene (1998) [Pubmed]
  4. High levels of p19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification. Hailat, N., Keim, D.R., Melhem, R.F., Zhu, X.X., Eckerskorn, C., Brodeur, G.M., Reynolds, C.P., Seeger, R.C., Lottspeich, F., Strahler, J.R. J. Clin. Invest. (1991) [Pubmed]
  5. Human T cell leukemia virus-I-associated T-suppressor cell inhibition of erythropoiesis in a patient with pure red cell aplasia and chronic T gamma-lymphoproliferative disease. Levitt, L.J., Reyes, G.R., Moonka, D.K., Bensch, K., Miller, R.A., Engleman, E.G. J. Clin. Invest. (1988) [Pubmed]
  6. Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d. Brotherton, D.H., Dhanaraj, V., Wick, S., Brizuela, L., Domaille, P.J., Volyanik, E., Xu, X., Parisini, E., Smith, B.O., Archer, S.J., Serrano, M., Brenner, S.L., Blundell, T.L., Laue, E.D. Nature (1998) [Pubmed]
  7. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Hirai, H., Roussel, M.F., Kato, J.Y., Ashmun, R.A., Sherr, C.J. Mol. Cell. Biol. (1995) [Pubmed]
  8. Chromosomes, genes, and development of testicular germ cell tumors. von Eyben, F.E. Cancer Genet. Cytogenet. (2004) [Pubmed]
  9. Identification of lamin B and histones as 1,25-dihydroxyvitamin D3-regulated nuclear phosphoproteins in HL-60 cells. Martell, R.E., Strahler, J.R., Simpson, R.U. J. Biol. Chem. (1992) [Pubmed]
  10. One INK4 gene and no ARF at the Fugu equivalent of the human INK4A/ARF/INK4B tumour suppressor locus. Gilley, J., Fried, M. Oncogene (2001) [Pubmed]
  11. Protein folding and stability of human CDK inhibitor p19(INK4d). Zeeb, M., Rösner, H., Zeslawski, W., Canet, D., Holak, T.A., Balbach, J. J. Mol. Biol. (2002) [Pubmed]
  12. Monoclonal antibody to human T-cell leukemia virus p19 defines polypeptide antigen in human choriocarcinoma cells and syncytiotrophoblasts of first-trimester placentas. Suni, J., Närvänen, A., Wahlström, T., Lehtovirta, P., Vaheri, A. Int. J. Cancer (1984) [Pubmed]
  13. Fine-structure analyses of lipid-protein and protein-protein interactions of gag protein p19 of the avian sarcoma and leukemia viruses by cyanogen bromide mapping. Pepinsky, R.B., Vogt, V.M. J. Virol. (1984) [Pubmed]
  14. Immunological characterization of the low molecular weight gag gene proteins p19 and p15 of human T-cell leukemia-lymphoma virus (HTLV) and demonstration of human natural antibodies to them. Kalyanaraman, V.S., Jarvis-Morar, M., Sarngadharan, M.G., Gallo, R.C. Virology (1984) [Pubmed]
  15. Alterations of the cyclin-dependent kinase inhibitor p19 (INK4D) is rare in hematopoietic malignancies. Shiohara, M., Spirin, K., Said, J.W., Gombart, A.F., Nakamaki, T., Takeuchi, S., Hatta, Y., Morosetti, R., Tasaka, T., Seriu, T., Bartram, C., Miller, C.W., Tomonaga, M., Koeffler, H.P. Leukemia (1996) [Pubmed]
  16. Gene expression profiling and identification of novel prognostic marker genes in neuroblastoma. Takita, J., Ishii, M., Tsutsumi, S., Tanaka, Y., Kato, K., Toyoda, Y., Hanada, R., Yamamoto, K., Hayashi, Y., Aburatani, H. Genes Chromosomes Cancer (2004) [Pubmed]
  17. DFNB68, a novel autosomal recessive non-syndromic hearing impairment locus at chromosomal region 19p13.2. Santos, R.L., Hassan, M.J., Sikandar, S., Lee, K., Ali, G., Martin, P.E., Wambangco, M.A., Ahmad, W., Leal, S.M. Hum. Genet. (2006) [Pubmed]
  18. FcepsilonRI-dependent gene expression in human mast cells is differentially controlled by T helper type 2 cytokines. Lora, J.M., Al-Garawi, A., Pickard, M.D., Price, K.S., Bagga, S., Sicoli, J., Hodge, M.R., Gutiérrez-Ramos, J.C., Briskin, M.J., Boyce, J.A. J. Allergy Clin. Immunol. (2003) [Pubmed]
  19. Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases. Okuda, T., Hirai, H., Valentine, V.A., Shurtleff, S.A., Kidd, V.J., Lahti, J.M., Sherr, C.J., Downing, J.R. Genomics (1995) [Pubmed]
  20. Structural organization, mapping, characterization and evolutionary relationships of CDKN2 gene family members in Xiphophorus fishes. Kazianis, S., Khanolkar, V.A., Nairn, R.S., Rains, J.D., Trono, D., Garcia, R., Williams, E.L., Walter, R.B. Comp. Biochem. Physiol. C Toxicol. Pharmacol. (2004) [Pubmed]
  21. HTLV in Sweden: antibodies to HTLV I antigens in experimental monkeys and their caretakers. Blomberg, J., Nilsson, I., Kjellén, L. Scand. J. Infect. Dis. (1985) [Pubmed]
  22. Antigen capture ELISA for HTLV I in cell culture. Bonfanti, C., Manca, N., Caruso, A., Gargiulo, F., Turano, A. Microbiologica (1989) [Pubmed]
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