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)

When treated with IFN-alpha, L1210 leukemia cells express high levels of the mouse 202 gene mRNA after a few hours. Three tandem copies of a 43 bp fragment (GAbox) homologous to the IFN-stimulatable response element (ISRE), located in the 5'-flanking region of the 202 gene, were linked to the reporter CAT gene and transiently transfected into L1210 cells. The data suggest that the GA box is sufficient to confer transcriptional inducibility upon IFN stimulation. Binding assays, using the labeled GA box as a probe, demonstrated the presence of a retarded complex, designated GAbfl, in the nuclear extracts of L1210 cells treated with IFN-alpha. This complex is absent in the extracts of L1210 cells treated with ssRNA viruses or synthetic dsRNA. Moreover, photoaffinity cross-linking experiments revealed that GAbfl contains a protein of about 50 kDa. Altogether these results demonstrate that antiviral state induction by IFN-alpha in L1210 cells is preceded by GAbfl binding to the ISRE of the IFN-inducible genes.
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PMID:Characterization of nuclear factors involved in 202 gene induction by IFN-alpha, viruses or dsRNA in murine leukemia cells. 786 82

Oxygen free radicals have been implicated in the pathogenesis of ischemic cell injuries. These free radicals are normally scavenged by antioxidant enzymes. Adenosine is normally released during ischemia and protects against ischemic injuries by interacting with adenosine receptors (ARs). The mechanism underlying its cytoprotective action is unclear. In this report, we provide evidence that activation of a unique A3AR in rat basophilic leukemia cells (RBL-2H3) leads to a 2 to 3 fold increase in activity of superoxide dismutase, catalase and glutathione peroxidase and also increases in the activity of glutathione reductase. Similar increases in enzyme activity were elicited in bovine and human endothelial cells, rat cardiac myocytes and smooth muscle cells. Increases in enzyme activity were attenuated by theophylline (an antagonist of the A3AR) and by pertussis toxin, implicating a role of A3AR/Gi protein in the activation. Importantly, activation of the A3AR decreased the degree of lipid peroxidation in these cells. These data provide strong evidence that the cytoprotective action of adenosine during ischemic cell injuries is mediated, at least in part, via a novel mechanism-activation of the cellular antioxidant enzymes.
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PMID:Adenosine acts as an endogenous activator of the cellular antioxidant defense system. 800 80

We have evaluated seven recently synthesized vitamin D3 analogs for their abilities to inhibit clonal growth of leukemic cells, to induce leukemic cell differentiation, to stimulate clonal growth of normal myeloid committed stem cells, and to transactivate a reporter gene having a 1,25(OH)2D3 response element (VDRE). The 1,25(OH)2-20-epi-D3 showed extraordinary activity; at 10(-11) mol/L it inhibited clonal growth of 87% of HL-60 myeloblast cells, 60% of S-LB1 cells (human T-cell lymphotropic virus type 1 [HTLV-1]-immortalized human T-lymphocyte cell line) and 50% of leukemic clonogenic cells (colony-forming unit-leukemia) obtained from patients with acute myelogenous leukemia. No effect of either 1,25(OH)2D3 or 1,25(OH)2-20-epi-D3 was observed on the clonal proliferation of an HTLV-1-immortalized human T-lymphocyte cell line (Ab-VDR) having nonfunctional 1,25 (OH)2D3 cellular receptors (VDR). The abilities of 1,25(OH)2-20-epi-D3 to induce differentiation of HL-60 cells, as measured by generation of superoxide and nonspecific esterase production, was less than its antiproliferative activities. This analog stimulated colony-forming unit-granulocyte-macrophage growth from normal human bone marrow. To gain insights into the remarkable antileukemic activities of 1,25(OH)2-20-epi-D3, we examined its ability to enter HL-60 cells, bind to the VDR, and interact with a transfected VDRE attached upstream of a TK promoter-driven reporter gene (chloramphenicol acetyl transferase [CAT]). The 1,25(OH)2-20-epi-D3 potently increased CAT activity (> 16-fold, as compared with cells transfected with control receptor having no VDRE); paradoxically, 1,25(OH)2-20-epi-D3 was of equal potency to 1,25(OH)2D3 in transactivating the VDRE-containing reporter gene, even though the analog had a 1,000-fold greater antileukemic effect as compared with 1,25(OH)2D3. In summary, we have identified an extremely potent 1,25(OH)2D3 analog with antiproliferative and differentiating effects on leukemic cells and that may be clinically useful. This analog appears to generate biologic responses via the classical VDR pathway, but further studies are required to elucidate the mechanism by which this analog produces its prominent activities.
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PMID:1 alpha,25-Dihydroxy-20-epi-vitamin D3: an extraordinarily potent inhibitor of leukemic cell growth in vitro. 808 Sep 98

To assess the influence of the 3' long terminal repeat (LTR) on the promoter/enhancer activity of the 5' LTR, a set of isogenic retroviral vectors differing only in the U3 region of the 3' LTR was constructed. These U3 elements were derived from viruses with different tissue tropism. The 5' LTR originated from Moloney murine leukemia virus and directed the transcription of a reporter gene (chloramphenicol acetyltransferase [CAT] gene), giving rise to plasmids of the general configuration LTR-CAT-LTR'. Following transfection of these chimeric constructs into various cell types, the CAT activity in a given cell line was inversely related to the activity of the downstream U3 region when used in a single-LTR construct in that cell type, indicating negative regulation of the 5' LTR by the chimeric 3' LTR'. Our data indicate that a highly active 3' LTR interferes with gene expression from the 5' LTR. Potential mechanisms for this down-regulation are discussed.
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PMID:Negative regulation of the 5' long terminal repeat (LTR) by the 3' LTR in the murine proviral genome. 813 43

Members of the NF-kappa B/Rel family of transcription factors are involved in the transcriptional regulation of numerous polypeptides important to the immune response and cellular growth. Several genes regulated in part by NF-kappa B/Rel such as interleukin 2, IL-2 receptor alpha, and GM-CSF are trans-activated via an indirect association with the HTLV-I Tax protein in virus-infected and transformed T cells. In this study, we have investigated the interactions between Tax and NF-kappa B/Rel in an attempt to elucidate the mechanism of Tax mediated trans-activation and its role in leukemogenesis. Transfection studies were performed in Jurkat T cells using expression vectors for individual NF-kappa B subunits and the Tax protein as well as an NF-kappa B regulated reporter plasmid. NF-kappa B proteins differentially trans-activated the HIV-1 enhancer-CAT reporter; co-expression of Tax abrogated the inhibitory effect of I kappa B alpha and a trans-dominant negative mutant of p65 (p65 delta), indicating that Tax was a trans-dominant activator of NF-kappa B-regulated genes. Co-immunoprecipitation studies with extracts from transfected cells and NF-kappa B and Tax subunit specific antibodies revealed that Tax did not co-immunoprecipitate with p50/p105, c-Rel, or I kappa B; however, antibody specific to p65 was able to co-immunoprecipitate a 40kDa protein from Tax-transfected cells. Previous studies have demonstrated a physical interaction between Tax protein and p100, indicating that Tax may preferentially associate with specific NF-kappa B proteins.
Leukemia 1994 Apr
PMID:Interactions between HTLV-I Tax and NF-kappa B/Rel proteins in T cells. 815 9

The murine c-myc gene contains two elements responsive to the rel-oncogene-related family of NF-kappa B factors. Previously we have shown that factor binding to these two NF-kappa B elements mediates induction of transcription of the c-myc promoter upon interleukin-1 treatment of human dermal fibroblasts and human T-cell leukemia virus type I tax gene expression in T cells (D. J. Kessler, M. P. Duyao, D. B. Spicer, and G. E. Sonenshein, J. Exp. Med. 176:787-792, 1992; M. P. Duyao, D. J. Kessler, D. B. Spicer, C. Bartholomew, J. L. Cleveland, M. Siekevitz, and G. E. Sonenshein, J. Biol. Chem. 267:16288-16291, 1992). To begin to delineate the specific roles of the individual members of the NF-kappa B family, here we have tested their effects on activation of a c-myc promoter/exon 1-CAT construct in NIH 3T3 cells. Classical NF-kappa B (p65/p50) was a potent transcriptional activator of the c-myc promoter. Cotransfection with either p65 alone or p65 in combination with p50 mediated significant induction. In contrast, expression of either v-rel or chicken c-rel failed to transactivate, while murine c-rel induced c-myc promoter activity only slightly. Furthermore, induction by classical NF-kappa B was inhibited by coexpression of either v-rel or chicken c-rel. Thus, individual members of the rel family have differential effects of the c-myc promoter, which can modulate overall transcriptional activity and allow for precise regulation of this oncogene under diverse physiologic conditions.
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PMID:Differential regulation of the c-myc oncogene promoter by the NF-kappa B rel family of transcription factors. 828 84

We examined the ability of hematopoietic cells to transactivate the HTLV promoter by a transcellular mechanism. HeLa cells containing a CAT reporter gene driven by the HTLV-2 promoter were cocultivated with hematopoietic cells of the B-(Raji), T-(HuT78, Jurkat) and monocyte/promyelocytic (THP-1, U937 and HL60) lineages. Cocultivation with U937 and HuT78 cells constitutively and significantly transactivated the HTLV-2 promoter, while no effect was observed with the other lines. However, activation of other T-cell lines (CEM, Jurkat, Molt-3 and MT-4) with a combination of phorbolester and phytohemagglutinin also resulted in potent transactivation. Supernatant from HuT78 cells exhibited detectable transactivating activity, suggesting that the activation is mediated by a secreted factor(s). This factor also transactivates the HTLV-1 promoter. We used a panel of HTLV-1 LTR deletion mutants to map the responsive elements to this factor(s). Unlike the response element to the HTLV transactivator protein, Tax, which can be mapped to a small region in the enhancer, maximal transactivation by the cellular factor(s) required the complete U3 sequence. Transcellular activation of the HTLV promoter by activated T-cells may play a role in the development of leukemia in HTLV infected individuals.
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PMID:Transcellular activation of the HTLV promoter by human hematopoietic cells. 830 96

The Tax1 protein of the human T-cell leukemia virus (HTLV-I) is a 40-kDa positive transactivator of viral gene expression. Tax1 does not bind directly to DNA, but associates indirectly with DNA via cellular transcription factors. To further investigate the activation of HTLV-I transcription by Tax1, a chimeric protein containing Tax1 fused to the DNA binding domain of Gal4 was created (Gal4-Tax). HTLV-I long terminal repeat (LTR) reporter plasmids were constructed in which specific Tax1 responsive elements were replaced with Gal4 binding sites. Cotransfection of Gal4-Tax or Tax1 with HTLV-I LTR reporter constructs containing Gal4 binding sites demonstrated that Gal4 sequences were necessary but not sufficient for maximal activation of the promoter by Gal4-Tax. Sequences surrounding the Gal4 binding sites were important in determining the level of Gal4-Tax activation. Association of Gal4-Tax with promoters which contained six Gal4 binding sites, but which lacked flanking LTR sequences, were weakly transactivated by Gal4-Tax (sevenfold). In contrast, LTR-CAT reporter constructs containing three Gal4 binding sites flanked by two 21 base pair repeat elements demonstrated a ninefold greater response to Gal4-Tax. These results suggest that cellular transcription factors, which bind the 21 base pair repeat elements, influence the ability of Tax1 to function as a transactivator. Furthermore, this effect is not fully explained by the ability of these factors to physically direct Tax1 to the LTR.
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PMID:Twenty-one base pair repeat elements influence the ability of a Gal4-Tax fusion protein to transactivate the HTLV-I long terminal repeat. 833 32

Murine leukemia L1210 cells grown for 2-3 weeks in the presence of 1% serum without selenium supplementation [L.Se(-) cells] typically exhibited < 10% of the glutathione peroxidase (GPX) and phospholipid hydroperoxide glutathione peroxidase (PHGPX) activity of selenium-satisfied controls [L.Se(+) cells]. Concomitant with diminished GPX and PHGPX activity was a 1.5- to 2.0-fold increase in catalase (CAT) activity, which reverted to control levels when L.Se(-) cells were given sufficient Se for full expression of selenoperoxidase activity. Selenium manipulation affected total glutathione content similarly, but had no effect on glutathione-S-transferase or superoxide dismutase activity. Long-term growth under Se-deficient conditions resulted in a progressive additional increase in CAT activity, which maximized after ca. 5 months. These cells [referred to as L'.Se(-)] attained CAT activity levels at least 100-times greater than those of Se-supplemented [L'.Se(+)] controls, whereas their glutathione content remained elevated by approximately 70%. Supplying L'.Se(-) cells with Se resulted in a rapid elevation to full GPX activity; however, CAT failed to decline in this case, suggesting that a selection for stable CAT hyperexpressing variants had been accomplished. Quantitative immunoblot analysis indicated that the high CAT activity of L'.Se(-) cells is accounted for by an elevated level of enzyme protein. Induction of CAT and selection for CAT-rich phenotypes, as apparent for Se-starved L1210 cells, was not observed in human K562 counterparts, which lack GPX and express only a low level of PHGPX. L.Se(-) cells were found to be more sensitive to H2O2-induced killing than L.Se(+) controls, whereas L'.Se(-) cells were exceedingly more resistant to H2O2 than L'.Se(+) counterparts. By contrast, L.Se(-) and L'.Se(-) cells were both more sensitive to t-butyl hydroperoxide than Se(+) controls, consistent with CAT being unimportant in the detoxification of this peroxide compared with GPX. This appears to be the first reported evidence for CAT hyperexpression in response to selenium deprivation.
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PMID:Hyperexpression of catalase in selenium-deprived murine L1210 cells. 834 49

The myelotoxicity, including leukemia, associated with benzene exposure has been attributed to the further activation of benzene-derived metabolites. In a previous study, we observed that (Cu(II) strongly mediates the oxidation of hydroquinone (HQ) producing benzoquinone (BQ) and H2O2 through Cu(II)/Cu(I) redox mechanism. Since copper exists in the nucleus and is closely associated with chromosomes and DNA, in this study we investigated whether this chemical--metal redox system induces strand breaks in phi X-174 RFI plasmid DNA. In the presence of micromolar concentrations of Cu(II) and HQ, both single and double strand breaks were induced, whereas HQ, Cu(II), H2O2 or BQ alone at the employed concentrations elicited no significant damage to DNA. The HQ/Cu(II) system was at least twice as efficient as a H2O2/Cu(II) system at inducing DNA strand breaks. Of Cu(II), Fe(III), Mn(II), Cd(II) and Zn(II), only HQ/Cu(II) induced extensive DNA strand breaks. Among HQ, 1,2,4-benzenetriol (BT), catechol and phenol, HQ/Cu(II) and BT/Cu(II) were the two most efficient DNA cleaving systems. The presence of bathocuproinedisulfonic acid (BCS) or catalase prevented the HQ/Cu(II)-induced DNA strand breaks. In addition, the HQ/Cu(II)-induced DNA strand breaks could be completely blocked by reduced glutathione and dithiothreitol, but not by L-cysteine. The interaction of L-cysteine with copper in the absence of HQ induced significant DNA strand breaks with the same pattern of DNA strand breaks as that of HQ/Cu(II) plus L-cysteine. In contrast to the HQ/Cu(II) system, a HQ/myeloperoxidase (MPO)/H2O2 system did not induce any DNA strand breaks, and furthermore, the presence of MPO inhibited the HQ/Cu(II)-induced DNA strand breaks. When DNA pretreated with Cu(II) was exposed to HQ, DNA strand breaks were formed that could be prevented by BCS or catalase, indicating that DNA-bound copper can undergo redox cycling in the presence of HQ, generating H2O2. Similar to the H2O2/Cu(II) system, the HQ/Cu(II)-induced DNA strand breaks could not be efficiently inhibited by hydroxyl radical scavengers but could be protected by singlet oxygen scavengers, indicating that the localized generation of singlet oxygen or a singlet oxygen-like entity, possibly a copper-peroxide complex, rather than free hydroxyl radical probably plays a role in the HQ/Cu(II)-induced DNA strand breaks. The above results suggest that macromolecule-associated copper and reactive oxygen generation may be important factors in the mechanism of HQ-induced DNA damage in target cells.
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PMID:DNA damage resulting from the oxidation of hydroquinone by copper: role for a Cu(II)/Cu(I) redox cycle and reactive oxygen generation. 839 44


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