Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of humans and experimental animals to benzene has been shown to result in hematotoxicity such as pancytopenia, aplastic anemia, and leukemia. The oxidative activation of the benzene metabolite, hydroquinone (HQ), in the bone marrow to the electrophilic benzoquinone (BQ) has been suggested to play an important role in benzene-induced hematotoxicity. Since the interaction of several xenobiotics with copper has been shown to result in their metabolism, in this study we have investigated the role of copper in the oxidation of HQ and HQ-induced toxicity to mice bone marrow stromal cells, target cells of HQ in the bone marrow. In phosphate-buffered saline, HQ underwent autoxidation slowly to BQ, while the presence of Cu(II) ions (1, 2.5, 5, 10, 50 microM) strongly accelerated the oxidation of HQ to BQ in a concentration-dependent manner. Reaction of HQ with Cu(II) was also accompanied by the reduction of Cu(II) to Cu(I), the utilization of O2, and the concomitant generation of H2O2. The oxidation of HQ by Cu(II) could be blocked by the Cu(I)-specific chelator bathocuproinedisulfonic acid (BCS), particularly when the ratio of BCS to Cu(II) was 4:1. By observing the kinetics of the reactions derived from mixing 100 microM HQ and 100 microM Cu(II), it was found that all of the Cu(II) was reduced to Cu(I) within 5 s, followed by consumption of O2 and the generation of BQ, which reached maximum levels at 4 min after mixing HQ and Cu(II). In addition, oxidation of HQ by Cu(II) also generated chemiluminescence. In the presence of myeloperoxidase, Cu(II)-mediated oxidation of HQ was increased. Addition of Cu(II) to primary bone marrow stromal cell cultures significantly enhanced HQ-induced cytotoxicity. The enhanced cytotoxicity of HQ by Cu(II) could be completely prevented by adding BCS, glutathione (GSH), or dithiothreitol but not by catalase. Supplementation of stromal cells with 20 microM BCS in the absence of exogenously added Cu(II) significantly abated HQ-induced cellular GSH depletion and cytotoxicity, suggesting a possible involvement of endogenous copper in the activation of HQ. The above results indicate that Cu(II) strongly induces the oxidation of HQ and as such may be a factor involved in the oxidative activation and toxicity of HQ in target cells.
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PMID:Oxidation of hydroquinone by copper: chemical mechanism and biological effects. 842 68

To characterize the interactions between human T-cell leukemia virus (HTLV) infection and cellular gene expression, we examined the expression of the lymphokine interleukin 3 (IL-3) in the presence and absence of HTLV infection. IL-3, like granulocyte-macrophage colony-stimulating factor (GM-CSF), is produced by activated but not resting T cells, but although GM-CSF is constitutively expressed in HTLV-infected T cells IL-3 mRNA cannot be detected in either unstimulated or mitogen-stimulated HTLV-infected cells by polymerase chain reaction (PCR) analysis. In contrast, transient co-transfection studies with an IL-3 promoter-CAT reporter gene and an HTLV-II Tax expression construct demonstrate that Tax can transactivate the IL-3 promoter in HTLV-uninfected T cells. To determine whether differences in IL-3 promoter-binding proteins present in HTLV-infected and uninfected T cells account for this discrepancy, DNAase I footprinting of the IL-3 promoter was performed. Although crude nuclear extracts from both cell types protected the IL-3 sequences located between base pairs -168 and -125, the sequences between -125 and -103, which contain the lymphokine consensus sequences CK-1 and CK-2, were protected by extracts from HTLV-infected but not HTLV-uninfected T cells. Deletion of the region containing the CK-1 and CK-2 sequences from an IL-3 promoter CAT construct resulted in a sixfold rise in promoter activity in HTLV-infected but not uninfected T-cell lines, indicating that this region participates in the repression of IL-3 gene expression in HTLV-infected T cells.
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PMID:Differential effect of HTLV infection and HTLV Tax on interleukin 3 expression. 851 Sep 34

Cyclic AMP (cAMP)-dependent protein kinase A (PKA) is known to have both negative and positive effects on the activation mechanisms of T lymphocytes. The authors have analysed the effect of increased cAMP on the activation of NF-kappa B transcription factor. This factor controls the expression of several genes (e.g. IL-2 and IL-2 receptor) involved in the activation and proliferation of T cells. The authors found that elevation of intracellular cAMP in Jurkat T leukaemia cells activated with phorbol ester (PDBu)/calcium ionophore (A23187) increased the DNA-binding of NF-kappa B as detected by the electrophoretic mobility shift assay (EMSA). Analysis of the subunit composition of the DNA-binding complex indicated that the amount of c-Rel was enhanced while RelA was decreased. Analysis of the effect of elevated cAMP on the degradation of I kappa B-alpha and I kappa B-beta did not reveal an essential change in degradation kinetics of these inhibitor proteins. The elevation of cAMP did not increase the synthesis of c-Rel, but it enhanced the nuclear localization of this protein. Transfection of Jurkat cells with a plasmid kB/TK10-CAT indicated that the increased DNA-binding of c-Rel containing complexes seen in EMSA was also functional. These data imply that the strong and long-lasting c-Rel nuclear localization and DNA-binding induced by protein kinase A is not due to increased c-Rel synthesis or enhanced degradation of the I kappa B inhibitors. Therefore, a direct phosphorylation of the c-Rel protein is the most plausible explanation for these observations. Taken together, these results suggest that cAMP is able to regulate the expression of NF-kappa B-dependent genes in T cells by modifying the composition and subunit activity of NF-kappa B.
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PMID:Activation of the protein kinase A increases the DNA-binding and transcriptional activity of c-Rel in T cells. 865 53

Specific binding of nuclear proteins to the region of transcriptional attenuation has been shown to modulate the expression of c-myb, a nuclear proto-oncogene preferentially expressed in lympho-hematopoietic cells. Here, it plays an important role in processes of differentiation and proliferation. The mechanism that regulates c-myb expression is not yet fully understood. The block of transcriptional elongation which has been mapped to a 1 kb region within murine intron 1 may represent one regulatory pathway. The DNA sequences containing the transcriptional pause site are well conserved between murine and human species, thus Implying similar transcription-control strategies. We compared the binding potential of nuclear extracts (from human fibroblasts and MOLT4 as well as murine NIH3T3- and 70Z/3B- cell lines) to oligonucleotide sequences previously shown to be target binding sites in the murine system. One complex containing a 70 D protein was found to be associated specifically with transcriptionally active leukemia cells. We performed transient expression studies with a CAT reporter construct containing this putative enhancer sequence and yielded significant CAT activity. We identified further a putative 20 kD repressor protein in transcriptionally silent cells and demonstrated that c-Jun is part of an ubiquitously present complex. Our results confirm the participation of intron 1 in transcriptional regulation of the c-myb gene (in mouse and human) and implicate multiple and complex regulatory mechanisms of activation during myelomonocytic differentiation and leukemic cell growth control.
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PMID:c-myb intron I protein binding and association with transcriptional activity in leukemic cells. 868 83

Adult T cell leukemia-derived factor (ADF) is a human thioredoxin (Trx) and is a disulfide reducing protein with various biological functions. We found that expression of the ADF/Trx gene was increased by oxidative agents such as hydrogen peroxide, diamide and menadione in Jurkat cells. Analysis using a CAT expression vector plasmid under the control of the ADF/Trx gene promoter revealed that CAT gene expression in Jurkat cells was increased after exposure to oxidative agents. A series of deletion analyses showed that a region from -976 to -890 of the 5' flanking sequence was required for enhancement of ADF/Trx promoter activity against the oxidative agents. Gel mobility shift assay revealed the specific DNA binding activities to the sequences from -953 to -930 in the nuclear extracts from the Jurkat cells. The sequences in this region showed no homology with any known consensus sequences for DNA binding factors. It is suggested that ADF/Trx gene expression is enhanced through a novel cis-acting regulatory element responsive for the oxidative stress and a new factor(s) is involved in this oxidative stress responsive element.
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PMID:A novel promoter sequence is involved in the oxidative stress-induced expression of the adult T-cell leukemia-derived factor (ADF)/human thioredoxin (Trx) gene. 875 6

Effects of selenium (Se) deficiency on the sensitivity of murine leukemia L1210 cells to broad band UVA/B radiation (310-400 nm) have been investigated. Cells rendered glutathione peroxidase (GPX) deficient by shortterm (2-3 week) growth in 1%, serum/RPMI medium without added Se [L.Se(-) cells] were found to be much less resistant to clonally assessed UVA/B lethality than Se-supplemented controls [L.Se(+) cells]. By contrast, long-term ( > 20 week) Se-deprived [L'.Se(-)] cells whose catalase (CAT) activity was elevated > 100-fold were far more resistant to UVA/B than L.Se(+) cells. Similar trends were observed for cells irradiated in 1% serum/RPMI or Hank's medium. Whereas the CAT inhibitor 3-amino-1,2,4-triazole had no effect on L.Se(+) photosensitivity, it produced a large increase in L'.Se(-) photosensitivity. These findings are consistent with H2O2 intermediacy in photokilling and suggest that L1210 cells depend mainly on GPX for protection against this species but switch to overexpressed CAT after chronic Se deprivation. In agreement with this, steady-state H2O2 levels measured by H2O2 electrode during UVA/B exposure were higher in L.Se(-) than L.Se(+) suspensions but much lower (barely detectable) in L'.Se(-) suspensions. Cytotoxic effects of UVA/B and variations thereof resulting from Se manipulation could be mimicked by treating cells with glucose oxidase in the presence of D-glucose, providing further support for H2O2 involvement. Whether UVA/B-generated H2O2 is directly cytotoxic or gives rise to a more damaging species such as hydroxyl radical (HO) is presently unknown.
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PMID:Role of hydrogen peroxide in the cytotoxic effects of UVA/B radiation on mammalian cells. 878 7

We compared the efficiency of human immunodeficiency virus (HIV-1) vectors that express a marker gene (chloramphenicol acetyltransferase, CAT) using different promoter elements. In one vector, CAT was expressed under the control of an internal murine leukemia virus (MuLV) long terminal repeat (LTR). In other vectors, CAT production was regulated by the HIV-1 LTR; these vectors also contained the HIV-1 tat gene and pol sequences reported to exert cis-acting positive effects on reverse transcription or gene expression. Vectors employing the Tat-driven HIV-1 LTR exhibited up to 500-fold greater CAT expression in Jurkat lymphocytes or human peripheral blood mononuclear cells compared with vectors using the internal MuLV LTR element as a promoter. This difference was not due to improved packaging of the vector RNA into virions, but to an improved level of gene expression in the target cells. Target cell CAT expression was two- to threefold higher for the vector containing the pol sequences and was only slightly less than that seen for a trans-complemented envdeleted provirus. These results indicate that defective HIV-1 vectors with efficiencies of gene transfer and expression comparable with that of HIV-1 itself are feasible.
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PMID:Use of cis- and trans-acting viral regulatory sequences to improve expression of human immunodeficiency virus vectors in human lymphocytes. 880 25

The expression of the human myeloid zinc finger gene (MZF-1) by human bone marrow cells is necessary for granulopoiesis. We have analyzed the structure and function of the MZF-1 gene by diagnostic polymerase chain reaction, genomic cloning, and promoter analysis. Comparison of human promyelocytic HL-60 cell cDNA with isolated MZF-1 genomic clones indicated that the human MZF-1 gene is without introns and spans approximately 3 kb. Restriction enzyme mapping and Southern analysis indicated further that the human MZF-1 gene is a single-copy gene. Primer extension studies identified the major transcription start site as a thymidine residue located 1102 bp upstream of the ATG translation start codon. A putative TATA box sequence (TAAAAA) was found at -66 bp and a CCAAT box at -130 bp relative to the transcription initiation site. In HL-60 cells, MZF-1 mRNA levels are increased by granulopoietic inducers including retinoic acid and GM-CSF. DNA upstream of the transcription start site contains tandem-repeated consensus retinoic acid response elements at -666 through -696 bp and paired putative GM-CSF-responsive sequences centered at -50 and -100 bp. CAT reporter gene constructs containing these DNA regions promoted transcription and conferred transcriptional responsiveness to retinoic acid and GM-CSF when transfected into HL-60 cells. Additional putative regulatory binding sites included conserved MZF-1 zinc finger binding sequences, the importance of which was suggested by the enhanced expression of the endogenous MZF-1 gene following vector-driven expression of MZF-1 constructs in K562 myeloblastic leukemia cells. These findings provide a clearer basis for understanding the role of MZF-1 gene expression in myeloid cell growth and differentiation.
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PMID:Isolation and functional characterization of the human gene encoding the myeloid zinc finger protein MZF-1. 884 78

Mucormycosis (zygomycosis) is an uncommon mycosis which can be contracted from the environment and which is responsible for rhino-orbital, pulmonary, gastrointestinal, cerebral or disseminated infections. Severe immunodepression, such as that caused by leukemia, lymphomata and organ graft, or treatment by desferrioxamine, may predispose to pulmonary and systemic forms. In the present work the authors describe a case of systemic mucormycosis, with unfavourable outcome, which arose in a pediatric peritoneal dialysis patient, then transferred to hemodialysis, without evident predisposing factors. In particular they refer to the CAT reports and to lymphonodal and peritoneal histological lesions which allowed them to attain the diagnosis.
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PMID:[Systemic mucormycosis in dialysis: computed tomography picture and histologic lesions]. 884 70

Adult T-cell leukemia-derived factor (ADF), identified in the supernatant of adult T-cell leukemia (ATL) cell culture, is a human homologue of thioredoxin and consists of 104 amino acids; it has two redox-active half-cysteine residues in an exposed active center. Human thioredoxin has many biological activities, including growth promotion, cell activation, and a catalase-like radical scavenging activity. We examined the protective effect of human thioredoxin (h-thioredoxin) against reperfusion-induced arrhythmias in an isolated rat heart model with 10-min regional ischemia followed by 30-min reperfusion. Male Wistar rats were assigned to six groups: a control, a superoxide dismutase (SOD 8 x 10(4) IU/L), and a catalase group (1 x 10(6) IU/L), and three groups treated with h-thioredoxin [approximately .01 microM (TRX-I group), approximately 0.1 microM (TRX-II group), and approximately 1 microM (TRX-III group)]. In the early reperfusion period, h-thioredoxin reduced the incidence of ventricular fibrillation (VF) to 8% in the TRX-II group (p < 0.01) from the control value of 75%. SOD and catalase reduced the incidence of VF to 43 and 33%, respectively (NS). During the entire reperfusion period, the incidence of VF in the SOD group was 79%, as compared to 83% in the control group. In the catalase and TRX-II groups, the incidence of VF was significantly reduced to 42 and 25%, respectively. These findings indicate that SOD failed to protect against the reperfusion-induced arrhythmias. h-Thioredoxin exerted a protective effect against these arrhythmias; a concentration of approximately 0.1 micro was the most effective.
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PMID:Protection against reperfusion-induced arrhythmias by human thioredoxin. 885 44


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