Autoantibodies to DEK oncoprotein in human inflammatory disease

Dong, Xingwen; Wang, Jingsong; Kabir, Fathima N.; Shaw, Melody; Reed, Ann M.; Stein, Leonard D.; Andrade, Luís Eduardo Coelho; Trevisani, Virgínia Fernandes Moça; Miller, Michael L.; Fujii, Tomoyuki; Akizuki, Masashi; Pachman, Lauren M.; Satoh, Minoru; Reeves, Westley H.

doi:10.1002/1529-0131(200001)43:1<85::aid-anr11>3.0.co;2-d

Cited by 58 publications

(44 citation statements)

References 30 publications

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“…Anti-DEK autoantibodies are found in the serum of patients with rheumatic and inflammatory disorders. 32 The t(6;9) translocation found in subsets of acute myelogenous leukemia involves fusion of DEK with the nucleoporin CAN. The link between the DEK-CAN fusion protein and leukemogenisis is not clear, however, t(6;9) is thought to be a marker of poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Defining a 0.5-Mb Region of Genomic Gain on Chromosome 6p22 in Bladder Cancer by Quantitative-Multiplex Polymerase Chain Reaction

Evans

Gallie

Jewett

et al. 2004

The American Journal of Pathology

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Urothelial carcinomas, or transitional cell carcinomas, represent the vast majority of human bladder cancers. Early molecular events associated with superficial bladder cancers include losses on chromosome 9p/9q and mutations in the p53 and retinoblastoma tumor suppressor genes. 1,2 The genomic alterations associated with disease progression, defined as the evolution of superficial bladder tumors to higher pathological stages, are complex and poorly understood. Conventional metaphase-based comparative genomic hybridization (CGH) has been used by several groups of investigators to study copy number imbalances in bladder cancer specimens of all stages and grades. These studies have illustrated the genomic complexity of bladder cancer and have identified recurrent regions of DNA copy number increase or high level amplification on several chromosomes including; 1q, 5p, 6p, 8q, 10p, 12q, 17q, and 20q. 3-9 These genomic regions are thought to contain oncogenes that may be important in tumor progression.Metaphase CGH studies have demonstrated copy number gains or high level amplifications at 6p22 in 7 to 55% of urothelial carcinomas, involving primarily the bladder, 3-9 but also those arising in the renal pelvis. 10 In addition, Bruch et al 11 reported 6p22 gains in 6 of 8 bladder cancer cell lines. Recently, Veltman et al 12 confirmed the metaphase CGH findings using array-based CGH to show copy number gains at 6p22 in 11 of a series of 41 bladder tumors. The changes at 6p22 in bladder cancer have been associated with high tumor cell proliferative activity, 9 tumors of high histological grade that are predominantly invasive, 3-9 and patients with distant metastases at initial presentation. 8 Based on these findings,

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Section: Discussionmentioning

confidence: 99%

Defining a 0.5-Mb Region of Genomic Gain on Chromosome 6p22 in Bladder Cancer by Quantitative-Multiplex Polymerase Chain Reaction

Evans

Gallie

Jewett

et al. 2004

The American Journal of Pathology

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“…This localizes CAN to the nucleoplasm rather than the nuclear membrane (Fornerod et al, 1995). In addition, DEK has been shown to be an autoantigen in a number of autoimmune disorders; the presence of anti-DEK antibodies correlates strongly with the development of pauci-articular juvenile rheumatoid arthritis (JRA), and even more specifically with cases involving ocular symptoms (Arnaudo et al, 1998;Dong et al, 2000;Murray et al, 1997;Sierakowska et al, 1993). DEK has also been linked to ataxia-telangiectasia, as a fragment of dek cDNA reverses the mutagen-sensitive phenotype that characterizes fibroblasts from patients with this disease (Meyn et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

YY1 and NF-Y binding sites regulate the transcriptional activity of the dek and dek-can promoter

2002

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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. The connection between DEK and cancer exists at multiple levels: (a) the t(6;9) chromosomal translocation that characterizes a subtype of acute myelogenous leukemia cases results in the formation of a DEK-CAN fusion oncoprotein; (b) a fragment of dek cDNA is capable of partially reversing the radiation-sensitive phenotype of fibroblasts cultured from ataxia-telangiectasia patients; and (c) increased levels of dek mRNA have been found to be associated with hepatocellular carcinoma, glioblastoma, and melanoma. Despite the growing list of cancer subtypes with a connection to DEK, the factors that mediate its expression have yet to be characterized. Here we undertake the analysis of DEK regulation by mapping the discrete elements within the proximal promoter that are responsible for constitutive transcription of dek in transformed cells. We find that functional elements include an inverted CCAAT box and a YY1 consensus binding site, and the introduction of point mutations into these sites markedly diminishes transcriptional activity. In addition, we identify the transcriptional activator NF-Y as a member of the CCAAT-binding complex, and verify binding of the transcription factor YY1 at its consensus site in the dek promoter. 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.

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“…Since its initial cloning, DEK or the immune response to DEK has been associated with several different cellular and pathologic processes. These include ataxia telangiectasia (11), pauciarticular onset juvenile rheumatoid arthritis (12), systemic lupus erythematosus (13)(14)(15)(16), sarcoidosis (13,15), idiopathic uveitis (15), and Kikuchi's disease (18).…”

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confidence: 99%

Protein Phosphatase 2A Activates the HIV-2 Promoter through Enhancer Elements That Include the pets Site

Faulkner¹,

Hilfinger²,

Markovitz³

2001

Journal of Biological Chemistry

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Human immunodeficiency virus type 2 (HIV-2) gene expression is regulated by upstream promoter elements, including the peri-Ets (pets) site, which mediate enhancer stimulation following treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). We previously showed that the oncoprotein DEK binds to the pets site in a site-specific manner. In this report, we show that binding to the HIV-2 pets site is modulated by treatment of U937 monocytic cells with TPA, an activator of protein kinase C. TPA treatment resulted in a reduction in the levels of DEK and the formation of a faster migrating pets complex in gel shift assays. We show further that the actions of TPA on pets binding can be duplicated by phosphatase treatment of nuclear proteins and is blocked with okadaic acid, a protein phospatase-2A (PP2A) inhibitor. Finally, we demonstrate that ectopic expression of the catalytic domain of PP2A can activate the HIV-2 enhancer/promoter alone or in synergy with TPA, an effect mediated in part through the pets site. These results suggest that, through an interaction with the protein kinase C pathway, PP2A is strongly involved in regulating HIV-2 enhancer-mediated transcription. This is a consequence of its effects on DEK expression and binding to the pets site, as well as its effects on other promoter elements. These findings have implications not only for HIV-2 transcription but also for multiple cellular processes involving DEK or PP2A.

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Autoantibodies to DEK oncoprotein in human inflammatory disease

Cited by 58 publications

References 30 publications

Defining a 0.5-Mb Region of Genomic Gain on Chromosome 6p22 in Bladder Cancer by Quantitative-Multiplex Polymerase Chain Reaction

Defining a 0.5-Mb Region of Genomic Gain on Chromosome 6p22 in Bladder Cancer by Quantitative-Multiplex Polymerase Chain Reaction

YY1 and NF-Y binding sites regulate the transcriptional activity of the dek and dek-can promoter

Protein Phosphatase 2A Activates the HIV-2 Promoter through Enhancer Elements That Include the pets Site

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