Disease relevance of DEK

• Overexpression of translocation-associated fusion genes of FGFRI, MYC, NPMI, and DEK, but absence of the translocations in acute myeloid leukemia. A microarray analysis [1].
• DEK was first identified in a fusion with the CAN nucleoporin protein in a specific subtype of acute myelogenous leukemia [2].
• DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer [2].
• Further, the last 65 amino acids of DEK can partially reverse the mutation-prone phenotype of cells from patients with ataxia-telangiectasia [2].
• In summary, our results suggest that DEK and E2F3 are potential targets of 6p gains in retinoblastoma [3].

High impact information on DEK

• We report here that the protein encoded by the proto-oncogene DEK, which is involved in acute myelogenous leukemia, induces alterations of the superhelical density of DNA in chromatin [4].
• The protein encoded by the proto-oncogene DEK changes the topology of chromatin and reduces the efficiency of DNA replication in a chromatin-specific manner [4].
• In this study, we demonstrate that DEK, together with SR proteins, associates with the SRm160 splicing coactivator in vitro [5].
• DEK is an approximately 45-kD phosphoprotein that is fused to the nucleoporin CAN as a result of a (6;9) chromosomal translocation in a subset of acute myeloid leukemias (AMLs) [5].
• Thus, DEK is a candidate factor for controlling postsplicing steps in gene expression that are influenced by the prior removal of an intron from pre-mRNA [5].

Biological context of DEK

• The discovery of NF-Y and YY1 as regulatory determinants of DEK expression is consistent with the well-documented roles of these two factors in cellular proliferation and transformation [6].
• Transcriptional activation by AP-2alpha is modulated by the oncogene DEK [7].
• The mammalian protein DEK has been implicated in multiple cellular processes, including transcriptional regulation, mRNA processing, and chromatin remodeling, and is associated with a number of clinical autoimmune and neoplastic conditions [6].
• Our findings show that DEK is a site-specific DNA binding protein that is likely involved in transcriptional regulation and signal transduction [2].
• DEK was originally described as a proto-oncogene protein and is now known to be a major component of metazoan chromatin [8].

Anatomical context of DEK

• Significantly, DEK remains bound to the exon-product RNA after splicing, and this association requires the prior formation of a spliceosome [5].
• We demonstrate the ability of recombinant DEK to bind specifically to the pets site using the electrophoretic mobility shift assay (EMSA) and DNase I footprinting. "Supershift" EMSA further confirms that DEK is the dominant protein binding to the pets site in T cell extracts [2].
• Cervical cancer cell senescence was partially overcome by DEK overexpression, and DEK overexpression was sufficient for extending the life span of primary keratinocytes, supporting critical roles for this molecule as a senescence regulator [9].
• We report here the specific repression of DEK message and protein levels in senescing human papillomavirus type 16- (HPV16-) and HPV18-positive cancer cell lines as well as in primary cells undergoing replicative senescence [9].
• We demonstrate here that DEK is actively secreted by macrophages and is also found in synovial fluid samples from patients with juvenile arthritis [10].

Associations of DEK with chemical compounds

• Recent data revealed that DEK associates with splicing complexes through interactions mediated by serine/arginine-repeat proteins [11].
• Furthermore, micrococcal nuclease digestion of nuclei followed by glycerol gradient sedimentation revealed that DEK co-sedimentates with oligonucleosomes, clearly demonstrating that DEK is associated with chromatin in vivo [11].
• Two of the interactors were the methyl CpG binding protein MeCP2 and the 43-kDa protein DEK [12].
• The DEK Nuclear Autoantigen Is a Secreted Chemotactic Factor [10].
• Secretion of DEK is modulated by casein kinase 2, stimulated by interleukin-8, and inhibited by dexamethasone and cyclosporine A, consistent with a role as a proinflammatory molecule [10].
• Knocking down p53 attenuated the effect of Nutlin-3 on DEK expression, whereas knocking down DEK significantly increased both spontaneous and Nutlin-3-induced apoptosis [13].

Physical interactions of DEK

• Finally, electrophoretic mobility shift assays suggested that DEK enhances the DNA-binding activity of AP-2alpha [7].
• These results indicate that several nonameric peptides derived from the DEK protein can bind to HLA-A 0201 and suggest that the complexes formed may be able to stimulate CD8+ T cells in patients with Pauciarticular Juvenile Arthritis [14].
• Measurement of the apparent dissociation constants demonstrated a two- to fivefold difference in DEK binding to the DQA1 Y-box sequence in comparison with other class II MHC Y-box sequences [15].

Other interactions of DEK

• Daxx and histone deacetylase II associate with chromatin through an interaction with core histones and the chromatin-associated protein Dek [16].
• SNP-based association studies of the region identified a 4-marker haplotype in the DEK gene that was significantly associated with RA (P = 0.009) [17].
• The remaining 20 (26%) samples showed gains only at some loci, most often including E2F3 and DEK in 6p22 [3].
• The t(6;9)(p23;q34) is a recurrent chromosomal abnormality observed in 1% of acute myelogenous leukemia (AML), which generates a fusion transcript between DEK and CAN/NUP214 genes [18].
• Most of the DEK protein was found to be released by DNase treatment of nuclei, and only a small amount by treatment with RNase [11].

Analytical, diagnostic and therapeutic context of DEK

• In searching for novel AP-2alpha- interacting factors, using an affinity chromatography approach, we have observed that oncoprotein DEK interacts with AP-2alpha in vitro [7].
• As shown by sedimentation analysis and electron microscopy, the DEK-induced positive supercoiling causes distinct structural changes of DNA and chromatin [19].
• To investigate the in vivo localization of DEK, we performed cell fractionation studies, immunolabeling, and micrococcal nuclease digestion analysis [11].
• E2F3 and DEK mRNA overexpression was always associated with protein overexpression, determined by immunoblotting or immunofluorescent staining of primary tumors, relative to the adjacent normal retina [20].
• Identification of the p33(ING1)-regulated genes that include cyclin B1 and proto-oncogene DEK by using cDNA microarray in a mouse mammary epithelial cell line NMuMG [21].

References