Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00001 (DNase I)
 8,324 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Moloney murine leukemia virus causes thymic leukemias when injected into newborn mice. A major genetic determinant of the thymic disease specificity of the Moloney virus genetically maps to two protein binding sites in the Moloney virus enhancer, the leukemia virus factor b site and the adjacent core site. Point mutations introduced into either of these sites significantly shifts the disease specificity of the Moloney virus from thymic leukemia to erythroleukemia (N. A. Speck, B. Renjifo, E. Golemis, T. Frederickson, J. Hartley, and N. Hopkins, Genes Dev. 4:233-242, 1990). We have purified several polypeptides that bind to the core site in the Moloney virus enhancer. These proteins were purified from calf thymus nuclear extracts by selective pH denaturation, followed by chromatography on heparin-Sepharose, nonspecific double-stranded DNA-cellulose, and core oligonucleotide-coupled affinity columns. We have achieved greater than 13,000-fold purification of the core-binding factors (CBFs), with an overall yield of approximately 19%. Analysis of purified protein fractions by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis reveals more than 10 polypeptides. Each of the polypeptides was recovered from an SDS-polyacrylamide gel, and those in the molecular size range of 19 to 35 kDa were demonstrated to have core-binding activity. The purified CBFs were shown by DNase I footprint analyses to bind the core site in the Moloney virus enhancer specifically, and also to core motifs in the enhancers from a simian immunodeficiency virus, the immunoglobulin mu chain, and T-cell receptor gamma-chain genes.
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PMID:Purification of core-binding factor, a protein that binds the conserved core site in murine leukemia virus enhancers. 130 96

Resistance to radiation leukemia virus-induced leukemia is mediated by gene(s) in the H-2D region of the MHC; a clear correlation exists between disease resistance and increased H-2Dd expression on the thymocyte surface. We have investigated the molecular basis for this stimulation of H-2Dd class I expression. Elevated H-2 mRNA and H-2 transcription are demonstrated in the infected thymocytes as compared to normal thymocytes indicating that the elevation of H-2 surface expression is the result of transcriptional activation. Gel mobility assays performed with nuclear extracts of normal and infected thymocytes and sequences 5' of the H-2Dd gene show that specific binding occurs with both extracts; the binding differs both quantitatively and qualitatively, however. DNase I protection analysis detects a protein binding site that is protected only by extracts from infected cells. The protected region contains a sequence similar to the AP-1 consensus sequence. Gel shift competition assays and UV photo-cross-linking to an oligonucleotide containing this sequence demonstrate that specific binding of an H-2 binding factor 1 occurs and that this factor is not the AP-1 binding complex. This novel binding factor, activated in vivo, might also be involved in the normal regulation of H-2 gene expression by recognizing the highly conserved binding sequence (TGACGCG) found in the 5' flanking region of many MHC class I genes. This is the first demonstration of the parallel stimulation of a DNA binding activity and increased transcription occurring in thymocytes after infection with a leukemogenic retrovirus.
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PMID:A novel DNA binding activity is elevated in thymocytes expressing high levels of H-2Dd after radiation leukemia virus infection. 163 76

The human CD7 molecule is a 40-kDa member of the immunoglobulin gene superfamily that is expressed on T-lymphoid and myeloid precursors in fetal liver and bone marrow. CD7 is also expressed on T lymphocytes in multiple stages of T-cell development, including a major subset of mature peripheral T cells. In this paper we report the isolation and characterization of the human CD7 gene and 5' flanking region. Sequence analysis revealed that the CD7 gene comprises four exons that span 3.5 kilobases. The 5' flanking region (506 base pairs) has a high G + C content and no "TATA" or "CCAAT" elements. DNase I sensitivity analysis of chromatin from the CD7+ progenitor cell leukemia line, DU528, and the CD7-, CD4+, CD8+, TCR alpha beta + T-cell line, DU980 (where TCR is the T-cell receptor), revealed two distinct hypersensitive sites 5' of the CD7 gene. Hypersensitive site 1, present in the DU980 T-cell line, was located 4.5 kilobases upstream of the presumed CD7 transcription initiation site. Only DNase I hypersensitive site 2, which mapped to the promoter region, was found in the DU528 line. Comparison of the organization of the CD7 gene with that of other members of the immunoglobulin gene superfamily revealed that the human CD7 gene most closely resembles the murine Thy-1 gene. Both CD7 and Thy-1 are encoded by small genes with four exons, contain TATA-less promoters, and have a similar functional organization. These structural similarities suggest that human CD7 and murine Thy-1 may be functional homologues.
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PMID:Isolation and characterization of the genomic human CD7 gene: structural similarity with the murine Thy-1 gene. 170 3

Early studies showed that resistance to RadLV-induced leukaemia is mediated by gene(s) in the H-2D region of the MHC. Furthermore, these experiments correlated disease resistance with changes in H-2 expression occurring very early after virus inoculation. In the present study, we have begun to study at the molecular level this stimulation of H-2Dd class I expression in thymocytes of resistant mouse strains following infection by RadLV. The resistant strain of B10.T(6R) mice is used in these studies. When these infected thymocytes are assayed by fluorescence-activated cell sorting analysis, we can detect increased levels of H-2Dd expression on the surface of the thymocytes as early as 12 days following intrathymic injection of RadLV. RNA was prepared and examined by Northern blot analysis; H-2 mRNA levels are shown to be elevated on the order of four-fold. Nuclei were prepared from normal and infected thymocytes and the run-off transcripts were analysed by slot-blot hybridization. The rate of H-2 mRNA transcription is shown to be two- to three-fold higher in RadLV-infected thymocytes at 14 days post-infection when compared to that of normal thymocytes. These data demonstrate that elevation of H-2 surface expression following RadLV infection is the result of transcriptional activation. Extracts have been prepared from both normal and infected B10.T(6R) thymocytes and have been used in gel mobility assays in order to detect the interaction of potential trans-acting regulatory factors with sequences 5' of the H-2Dd gene. Specific binding occurs in both extracts, but the assay shows that the extracts differ both quantitatively and qualitatively; the extracts from infected thymocytes bind to additional sequences and to a higher degree than that from normal thymocytes. DNase I protection analysis locates a number of protein-binding sites, some of which are protected by extracts of either origin and some of which are only protected by extracts from infected cells. Two of these sequences are similar to the previously recognized consensus recognition sequences for the binding of AP-1 and NF-chi B. Oligonucleotides have been synthesized for both the genomic sequences being protected from DNase I digestion as well the published consensus sequences. While the DNA-binding activity in infected thymocytes for both AP-1 and NF-chi B-binding sites is increased, the binding to the genomic "AP-1 like" binding site is activated to a considerably greater level.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vivo stimulation of H-2Dd expression following RadLV infection of thymocytes: increased transcription and DNA-binding activity to sequences 5' of the Dd gene. 175 16

PMA treatment of human leukemic cells resulted in a significant increase in the phosphorylation of a 72-kDa protein, which was abrogated by treating the nuclear extracts with DNase I, but additionally stimulated by adding DNA. To be active, DNA must be double-stranded with an average size of 300 base pairs, but shows no apparent species- or sequence-specificity. NP-72 isolated from control or PMA-treated nuclei with 1 mM ATP lacked phosphorylating activity, suggesting it to be a substrate for a dsDNA-stimulated protein kinase(s). Simultaneous exposure of HL-60 cells to PMA and the protein kinase C inhibitor staurosporine diminished the phosphorylation of NP-72. These data suggest that leukemia cell differentiation is accompanied by the induction and/or activation of a dsDNA-stimulated protein kinase whose protein substrates include NP-72 and whose activity is directly or indirectly influenced by protein kinase C.
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PMID:dsDNA-stimulated phosphorylation of a 72-kDa nucleoprotein accompanies PMA-induced HL-60 leukemic cell differentiation. 177 55

The level of myeloperoxidase (MPO) mRNA is reduced significantly after HL-60 induced differentiation with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). We examined the chromatin structural changes of the MPO gene during TPA induction. Before TPA induction about nine DNase I hypersensitive sites (HS) were found on the 5' upstream and at various intron regions of the MPO gene. A new HS was found on intron 8 within 4 h of induction; its appearance preceded down regulation of the MPO gene. At the same time DNase I HS found in 0.3 and 1-1.5 kb upstream of the MPO CAP site, were significantly reduced or disappeared after TPA induction. These chromatin structural changes could be closely linked to the mechanism which regulates the MPO gene expression.
Leukemia 1991 Mar
PMID:Down regulation of myeloperoxidase gene associated with specific nuclease hypersensitive sites during TPA induced differentiation of HL-60. 184 1

We present a map describing the binding of cellular proteins to a 300-base pair (bp) region of the human T-cell leukemia virus type I (HTLV-I) long terminal repeat. The map accounts for nearly all of the DNase I protection reported in a previous study using crude nuclear extracts. Notable features include a complex arrangement of overlapping binding sites encompassing the 21-bp repeat elements (see accompanying paper) as well as binding sites for the transcription factors Sp1 and NF-I that significantly deviate from the previously defined consensus recognition sequences. Based on the binding results, we constructed simple chimeric promoters containing 21-bp repeat elements, Sp1-, and nuclear factor I-binding sites upstream of a TATA box. Transient transfection experiments show that these promoters are expressed in T-cells and are regulated by the viral tax2 gene product. Deletion of the Sp1 and nuclear factor I sites abolishes tax-induction, suggesting that one or both of these proteins play a role in mediating the tax-responsiveness conferred by the 21-bp repeat element.
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PMID:Interaction of host cell proteins with the human T-cell leukemia virus type I transcriptional control region. II. A comprehensive map of protein-binding sites facilitates construction of a simple chimeric promoter responsive to the viral tax2 gene product. 218 38

The distribution of primer RNA and RNA-primed nascent DNA in nuclei of CCRF-CEM leukemia cells was examined, and the primer RNA purified from the nuclear matrices of these cells was characterized. RNA-primed nascent DNA was radiolabeled by incubating whole-cell lysates with [alpha-32P]ATP and [3H]dTTP in the presence of approximately physiological concentrations of the remaining ribo- and deoxyribonucleoside triphosphates. The primer RNA was purified by cesium chloride density gradient centrifugation and analyzed by polyacrylamide gel electrophoresis. Nuclear subfractionation studies revealed that at least 94% of the primer RNA and RNA-primed nascent DNA were located within the insoluble matrix fraction of the nucleus. The predominant primer RNA isolated from the nuclear matrix was 8-10 nucleotides in length, and several lines of evidence indicated that this oligoribonucleotide was the functional primer RNA. Essentially all of the matrix primer RNA was covalently linked to the newly replicated DNA as demonstrated by its buoyant density in cesium chloride gradients, phosphate-transfer analysis, and sensitivity to DNase I. Analysis of 32P transfer from [alpha-32P]dTTP revealed a random distribution of ribonucleotides at the 3'-end of the primer RNA. Data obtained from mixing experiments indicated that the association of RNA-primed nascent DNA with the nuclear matrix was not the result of aggregation of these fragments with the nuclear matrix. No significant amount of either primer RNA, RNA-primed nascent DNA, or phosphate transfer was detected in the high-salt-soluble (nonmatrix) fraction of the nucleus, although the nonmatrix fraction contained most of the newly replicated DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synthesis and distribution of primer RNA in nuclei of CCRF-CEM leukemia cells. 219 15

The Philadelphia (Ph1) chromosome (22q-), found in more than 90% of patients with chronic myeloid leukemia (CML), is one part of a reciprocal translocation, t(9;22) (q34;q11), in which the oncogene c-abl moves from 9q34 to 22q11. The translocation results in the translation of an aberrant abl-related protein with tyrosine kinase activity. Genetically active genes are known to have chromatin which is hypersensitive to deoxyribonuclease I (DNase I) and to be hypomethylated. Using an in situ nick translation technique on metaphase chromosomes, we have examined DNase I sensitivity and methylation status at the breakpoints 9q34 and 22q11 in bone marrow cells from controls (two cases) and CML patients (three cases). In CML cells DNase I sensitivity was significantly increased, at both breakpoints, in the translocated chromosomes compared with their normal homologues in CML cells and with both homologues in control marrows. A hypermethylated site, seen at 22q11 in normal 22s was hypomethylated on 22q-. The 9q34 region was hypomethylated in normal and translocated chromosomes. DNase I sensitivity, seen at 22q13 in CML cells, was lost following translocation in one of three cases. This technique demonstrates alterations in chromatin conformation and methylation status at translocation breakpoints which may be related to acquired genetic activity at one or both of these sites.
Leukemia 1990 May
PMID:Possible evidence for acquired genetic activity at both chromosomal breakpoints of the Philadelphia translocation in chronic myeloid leukemia. 238 79

We have used Abelson murine leukemia virus (A-MuLV) transformed pre-B cell lines to test the hypothesis that the rearrangement potential of a developing B-lymphocyte is dependent on an "opening" of the chromatin structure surrounding immunoglobulin (Ig) genes, thus allowing accessibility to an Ig gene recombinase. The chromatin structures surrounding heavy (H), kappa (kappa), and lambda (lambda) chain constant-region genes were assessed by DNase I sensitivity in A-MuLV transformed cell lines capable of H, kappa or lambda gene rearrangement. Our results indicate that DNase I-sensitive chromatin structures of these Ig constant-region genes correlate closely with the ability of the genes to undergo recombination. We also find that the chromatin structure of an Ig constant-region locus becomes DNase I sensitive before any DNA rearrangement events occur.
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PMID:DNase I sensitivity of immunoglobulin light chain genes in Abelson murine leukemia virus transformed pre-B cell lines. 254 57


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