Expression of the human neutrophil elastase gene: Positive and negative transcriptional elements in the 5′ flanking region

Han, Jian; Unlap, Tino; Rado, Thomas A.

doi:10.1016/0006-291x(91)92104-r

Cited by 15 publications

(7 citation statements)

References 11 publications

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“…Interestingly, reasonable matches were found in the promoters for myeloperoxidase and neutrophil elastase, genes that match this description (30,31). Preliminary data indicate that DEK does bind to these somewhat divergent pets-like sites in the neutrophil elastase and myeloperoxidase promoters (not shown).…”

Section: Discussionmentioning

confidence: 68%

DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer

Grosveld

Markovitz

1997

Proc. Natl. Acad. Sci. U.S.A.

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The product of the dek oncogene is the 43-kDa DEK nuclear protein. DEK was first identified in a fusion with the CAN nucleoporin protein in a specific subtype of acute myelogenous leukemia. DEK has also been shown to be an autoantigen in patients with pauciarticular onset juvenile rheumatoid arthritis. Further, the last 65 amino acids of DEK can partially reverse the mutation-prone phenotype of cells from patients with ataxia-telangiectasia. However, in spite of these significant disease associations, the function of DEK has remained unclear. The HIV-2 peri-ets (pets) site is a TG-rich element found between the two Elf-1 binding sites in the HIV-2 enhancer. The pets element mediates transcriptional activation whether the enhancer is stimulated by phorbol 12-myristate 13-acetate (PMA) alone, phytohemagluttinin (PHA) alone, PMA plus PHA, soluble antibodies to the T cell receptor, immobilized antibodies to the T cell receptor, or by antigen. Previously, we purified and characterized the pets factor, demonstrating that it is a 43-kDa nuclear protein. We now describe the identification of DEK as this 43-kDa pets factor. Using a modified Southwestern screening procedure, we find that DEK can recognize the pets element. 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. Our findings show that DEK is a site-specific DNA binding protein that is likely involved in transcriptional regulation and signal transduction. This has implications for multiple pathogenic processes, including hematologic malignancies, arthritis, ataxia-telangiectasia, and AIDS caused by HIV-2.A (6;9) chromosomal translocation is associated with a specific subtype of acute myelogenous leukemia (AML) (1-3). This translocation results in the fusion of two genes, dek and can, and the expression of a leukemia-specific, chimeric dek-can mRNA and fusion protein (1). How this 165-kDa chimeric protein might lead to leukemia has been unclear, however. It has recently been shown that CAN is a nucleoporin, and it has therefore also been termed nup214 (nucleoporin of 214 kDa; ref. 4). The 3Ј portion of CAN can form a fusion protein not only with DEK, leading to AML, but also with the SET protein, leading to undifferentiated leukemia (2). One group has shown that CAN localizes exclusively to the cytoplasmic side of the nuclear pore complex (4). A second group has demonstrated that, when CAN is overexpressed, it is found not only on the cytoplasmic side of the nuclear membrane, but also on the nucleoplasmic side (5). Like their normal counterparts DEK and SET, DEK-CAN, and SET-CAN were localized exclusively to the nucleus. It was concluded that the relocation of the carboxyl-terminal portion of CAN from the nuclear envelope to the nucleoplasm may reinforce a nuclear function of CAN (5), implying that this relocation plays a role in l...

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Section: Discussionmentioning

confidence: 68%

DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer

Grosveld

Markovitz

1997

Proc. Natl. Acad. Sci. U.S.A.

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“…1 which has an important role in regulating the myeloid-specific expression of the CD 11 b and lysozyme genes [ 17,181. Region II contains the glucocorticoid regulating element-like sequence (AGAACAN,TGlTCT)[lS], and region III seems to contain the pyrimidine-rich sequence which is assumed to be a regulatory element of the myeloperoxidase and neutrophil elastase genes [20].…”

Section: Resultsmentioning

confidence: 99%

Characterization of the promoters of the guinea pig neutrophil cationic peptide‐1 and ‐2 genes

1994

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Guinea pig neutrophils contain the antimicrobial cationic peptides GNCP-1 and GNCP-2 in the granules. To understand the regulation of the gene expression, the promoters for the GNCP-1 and GNCP-2 genes were characterized. Sequencing analysis of the genomic clones showed that the nucleotide sequences of the 5'-upstream regions (1.7 kb) from exon 1 were homologous @O-93%) between the GNCP-1 and GNCP-2 genes. However, transient transfection assays using luciferase reporter gene constructs revealed that the promoter activity of GNCP-1 was 2-fold greater than that of GNCP-2. Furthermore, DNase I footprint analysis demonstrated that three regions (I, II and III) were protected on the GNCP-1 promoter, whereas only two protected regions (II and III) were identified on the GNCP-2 promoter. Together these observations indicate that GNCP-1 and GNCP-2 are encoded by homologous genes, but the expression of the GNCP-1 and GNCP-2 genes is likely to be different at the level of transcription.

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“…Cis-acting DNA elements important for the regulation of the neutrophil elastase gene (18), the myeloperoxidase gene (19)(20)(21), and the promyelocytespecific mim-1 gene (22) have been identified; however, the roles of these cis-acting elements for promyelocyte-specific targeting in transgenic animals have not been defined. Some information is available about transcription factors that bind to regulatory elements within or near these genes.…”

mentioning

confidence: 99%

“…Some information is available about transcription factors that bind to regulatory elements within or near these genes. For example, (i) an upstream element of the neutrophil elastase gene appears to be recognized by Ets family members (18), (ii) a regulatory element upstream from the myeloperoxidase promoter is recognized by the partially characterized MyNF-1 factor (21), and (iii) the mim-1 5' flanking region contains binding sites for Myb, Ets, and C/EBP transcription factors (22)(23)(24). Although the 5' flanking regions for human and mouse CG genes contain several conserved elements (7,10), the functional significance of these elements, and the proteins that bind them, have not been characterized in detail.…”

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confidence: 99%

Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice.

Grisolano

Sclar

Ley

1994

Proc. Natl. Acad. Sci. U.S.A.

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The human cathepsin G (CG) gene is expressed only in promyelocytes and encodes a neutral serine protease that is packaged in the azurophil (primary) granules of myeloid cells. To define the cis-acting DNA elements that are responsible for promyelocyte-speciflc "targeting," we nijected a 6-kb transgene containing the entire human CG gene, including coding sequences contained in a 2.7-kb region, -2.5 kb of 5' flanking sequence, and "0.8 kb of 3' flanking sequence. Seven of seven "transient transgenic" murine embryos revealed human CG expression in the fetal livers at embryonic day 15. Stable trangenic founder lines were created with the same 6-kb fragment; four of five founder lines expressed human CG in the bone marrow. The level of human CG expression was relatively low per gene copy when compared with the endogenous murine CG gene, and expression was integration-site dependent; however, the level of gene expression correlated roughly with gene copy number. The human CG transgene and the endogenous murine CG gene were coordinately expressed in the bone marrow and the spleen. Immunohistochemical analysis of trngenic bone marrow revealed that the human CG protein was expressed exclusively in myeloid cells. Expression of human CG protein was highest in myeloid precursors and declined in mature myelold cells.These data suggest that the human CG gene was appropriately targeted and developmentally regulated, demonstrating that the cis-acting DNA sequences required for the early myeloid cell-specific expression of human CG are present in this small genomic fragment.

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Expression of the human neutrophil elastase gene: Positive and negative transcriptional elements in the 5′ flanking region

Cited by 15 publications

References 11 publications

DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer

DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer

Characterization of the promoters of the guinea pig neutrophil cationic peptide‐1 and ‐2 genes

Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice.

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