Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potential role of tumor necrosis factor alpha (TNF alpha), interferon alpha (IFN alpha) and interferon gamma (IFN gamma) in the therapy of non-lymphoid leukemia was studied in ten non-lymphoid leukemia cell lines. All three cytokines tested inhibited the growth of the cell lines. However, a high degree of variability in susceptibility to cytotoxic/cytostatic effect of the cytokines was found among individual cell lines. Some cell lines were sensitive to the antiproliferative action of only one of the cytokines tested, but were resistant to the others. Combinations of two cytokines had additive or synergistic effects and inhibited cell growth to a greater extent than did the individual cytokines alone. In addition to the growth-inhibitory effect, the cytokines induced an apparent cell differentiation. The differentiation of the two most sensitive cell lines, EoL-1 and PL-21, was confirmed using the nitroblue tetrazolium reduction test, by changes in cell morphology, immunophenotype marker profiles and by changes in c-myb expression. Furthermore, we showed that even in the cell lines relatively resistant to the antiproliferative effect of cytokines, such as cell line KCL-22, the inhibition of cell growth could be markedly increased with the DNA-topoisomerase-II-targeted drug, doxorubicin. Our data thus suggest that TNF alpha, IFN alpha and IFN gamma together have a potential role in the immunotherapy of non-lymphoid leukemia in terms of their antiproliferative action, and their ability to induce differentiation and to modulate drug sensitivity.
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PMID:Effects of tumor necrosis factor alpha, interferon alpha and interferon gamma on non-lymphoid leukemia cell lines: growth inhibition, differentiation induction and drug sensitivity modulation. 151 60

In a search for factors that influence the process of erythroid differentiation at the molecular level, we have identified UB2, a nuclear protein factor that was originally observed for its ability to bind to a very specific and highly conserved sequence motif present in human, mouse, rabbit, and chicken beta-globin genes, as well as carbonic anhydrase I, c-myb, and the immunoglobulin heavy chain enhancer region. It was also observed for its appearance in undifferentiated but not differentiated mouse erythroleukemia cells. Purification of UB2 by DEAE-cellulose chromatography and repeated passages through a DNA affinity column, revealed a complex pattern with three major components of 170, 116, and 48 kDa, respectively. The 170-kDa protein was identified as topoisomerase (topo) II by Western blot analysis, catalytic assays, and antibody interference with UB2 binding. The complex topo II in UB2, however, has a more stringent sequence requirement for DNA binding than does topo II. The 116-kDa protein has been determined to be a proteolytic product of topo II. The chromosome scaffold protein 2 (135 kDa) copurified with UB2, and anti-scaffold protein 2 serum inhibited UB2 binding to DNA.
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PMID:Purification and characterization of a nuclear DNA-binding factor complex containing topoisomerase II and chromosome scaffold protein 2. 838 2

The antitumor activity of pMC540 has been shown to be mediated via its interaction with topoisomerase (Topo) II eventually leading cells into apoptosis. This agent was also found to down regulate the expression of the c-myc oncogene in L1210 leukemia cells. To investigate the possibility that damage within select genomic regions may contribute to the antiproliferative activity of pMC540, differential damage in regions surrounding the c-myc locus as well as other select genes was determined. Southern blot hybridization experiments show that pMC540 treatment induces in situ DNA cleavage products in the 5' end of the c-myc oncogene of L1210 leukemia cells. In cells pre-treated with 50 microM ethidium bromide, an inhibitor of the Topo II-dependent DNA cleavage, a subsequent treatment with pMC540 failed to induce DNA cleavage, suggesting that the cleavage activity of pMC540 was Topo II dependent. pMC540-induced cleavage does not appear to correlate with the over-expression of the c-myc oncogene in these cells as another over-expressed gene c-myb was not affected. Thus, it is proposed that the c-myc gene may be a preferred target for pMC540 may mediated antiproliferative activity.
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PMID:In situ stimulation of topoisomerase II-induced cleavage sites in the c-myc protooncogene by antitumor agent pMC540 is associated with gene expression. 879 3

DNA topoisomerase IIalpha (topo IIalpha) is an essential proliferation-dependent nuclear enzyme which has been exploited as an anti-tumor drug target. Since the proliferative status of human leukemia cells is associated with expression of the c-myb proto-oncogene, c-Myb was investigated as a trans-activator of the topo IIalpha gene. Using topo IIalpha promoter-luciferase reporter plasmids, c-myb expression caused trans-activation of the topo IIalpha promoter a maximum of approximately 4.5-fold over basal levels in HL-60 human promyelocytic leukemia cells. Trans-activation was submaximal with higher levels of c-myb expression plasmid but a Myb protein lacking its negative regulatory domain resulted in approximately 19-fold trans-activation. Mutagenesis and 5'-deletion studies revealed that Myb trans-activation was mediated via a Myb-binding site at positions -16 to -11 and that this region governed the bulk of basal topo IIalpha promoter activity in human leukemia cells. Trans-activation of topo IIalpha by c-Myb was lymphoid- or myeloid-dependent. However, B-Myb, a more widely-expressed Myb family member, caused topo IIalpha trans-activation in both HL-60 cells and HeLa epithelial cervical carcinoma cells. These data provide evidence for a new Myb-responsive gene which is directly linked to and required for cellular proliferation.
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PMID:c-Myb trans-activates the human DNA topoisomerase IIalpha gene promoter. 904 45

Besides established mechanisms involved in cellular drug resistance including P-glycoprotein overexpression, topoisomerase alterations and xenobiotic detoxification, the hypothesis that proto-oncogene activation might also play a role in cell resistance has been postulated. This hypothesis has been tested by comparing the expression of various proto-oncogenes involved in signal transduction pathways (c-H-ras, c-g-ras, c-mil, c-myc, c-myb, c-fos), as well as the mdr gene and a tumor suppressor gene (p53) in different adriamycin-resistant (acquired or de novo) or sensitive cell lines, The implication of these variations in the process of chemoresistance is discussed.
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PMID:Expression of a tumor-suppressor gene and of various protooncogenes in human and murine adriamycin-resistant and sensitive cell-lines. 2155 66