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

• We now report that a monoclonal IgG antibody specific for the p19 protein of human T-cell leukemia virus (HTLV) reacts with human syncytiotrophoblastic antigen [12].
• Monoclonal antibody to human T-cell leukemia virus p19 defines polypeptide antigen in human choriocarcinoma cells and syncytiotrophoblasts of first-trimester placentas [12].

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].

References