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

The Tax I trans-activator protein of the human T-cell leukemia virus I (HTLV-I) enhances viral gene expression through enhancer sequences in the viral LTR. These sequences consist of three imperfect 21-bp repeats (TRE-1) and a region between the promoter central and promoter proximal TRE-1 (known as TRE-2). We have previously described the in vivo footprint of the HTLV-I TRE-1s and TRE-2 in two HTLV-I-infected cell lines, MT-2 and MT-4. MT-2 is a high-level producer of virus and shows significant DNA-protein interactions within the TRE-1s and TRE-2. In contrast, the proviral DNA in MT-4 cells is heavily methylated and produces no detectable virus. In this report, we describe the footprints of the TRE-1s and TRE-2 in MT-4 cells that were induced to express high levels of viral proteins by treatment with 5-azacytidine, a potent inhibitor of methylation. The footprints of the TRE-1s in 5-azacytidine-treated MT-4 cells were virtually identical to those observed in MT-2 cells. In contrast, the footprints within the TRE-2 region of 5-azacytidine-treated MT-4 cells did not resemble those in either MT-2 or MT-4 cells.
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PMID:Induction of Tax i expression in MT-4 cells by 5-azacytidine leads to protein binding in the HTLV-1 LTR in vivo. 1133 46

Murine cells do not support efficient assembly and release of human immunodeficiency virus type 1 (HIV-1) virions. HIV-1-infected mouse cells that express transfected human cyclin T1 synthesize abundant Gag precursor polyprotein, but inefficiently assemble and release virions. This assembly defect may result from a failure of the Gag polyprotein precursor to target to the cell membrane. Plasma membrane targeting of the precursor is mediated by the amino-terminal region of polyprotein. To compensate for the assembly block, we substituted the murine leukemia virus matrix coding sequences into an infectious HIV-1 clone. Transfection of murine fibroblasts expressing cyclin T1 with the chimeric proviruses resulted in viruses that were efficiently assembled and released. Chimeric viruses, in which the cytoplasmic tail of the transmembrane subunit, gp41, was truncated to prevent potential interference between the envelope glycoprotein and the heterologous matrix, could infect human and murine cells. They failed to further replicate in the murine cells, but replicated with delayed kinetics in human MT-4 cells. These findings may be useful for establishing a murine model for HIV-1 replication.
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PMID:Chimeric human immunodeficiency virus type 1 containing murine leukemia virus matrix assembles in murine cells. 1173 11

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to interact with several transcription factors and regulate their transcriptional activities. The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein activates transcription from its long terminal repeat (LTR) through interaction with cellular factors such as CREB and a transcriptional coactivator CBP/p300. However, little is known about the interaction between Tax and transcriptional repressors. Here, we demonstrate the physical and functional interaction between Tax and HDAC1. We found that HDAC1 represses the trans-activation function of Tax in 293T and MT4 cells. However, this repression was restored by treatment with an HDAC inhibitor, Trichostatin A. We also observed physical interaction between Tax and HDAC1 both in vitro and in vivo. The N-terminal region of HDAC1 (amino acid residues 28-97) was required for this binding. Moreover, HDAC1 inhibited the synergistic trans-activation of Tax observed on ectopic expression of CBP. However, this repression was relieved by overexpression of CBP. Thus, HDAC1 is likely to compete with CBP in binding with Tax and functions as a negative regulator for the transcriptional activation by Tax.
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PMID:The interaction of HTLV-1 Tax with HDAC1 negatively regulates the viral gene expression. 1237 Aug 15

Cytokine mRNA expression was studied in human long-term cell cultures of different origin: J-96 and J-41 (monocytic leukemia), SW-13 (paradrenal adenocarcinoma), and MT-4 (T-cell leukemia), in response to IFN-alpha and IFN inducers (kagocel and cycloferon). Cytokine mRNA level in the cell cultures was measured by the RT-PCR method using 11 primer pairs for the following cytokines: IFN-alpha, IFN-gamma, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18 and TNF-alpha. It was shown that IFN-alpha and IFN inducers possess an ability to regulate different cytokine mRNAs. Treatment of the cells with IFN-alpha resulted in expression of mRNAs for IL-2, IL-4, and IL-8. Kagocel induced production of IFN-alpha, IFN-gamma, and IL-2 mRNAs, and cycloferon--IFN-gamma, IL-2, IL-4, and IL-8 mRNAs. It is suggested that antiviral effects of these inducers, in general, can be attributed to imitation of cytokine responses observed in viral infection and, as a result, can lead to starting-up of cellular defense antiviral mechanisms even before action of viruses. Conclusion is made that IFN and IFN inducers may act as regulators of cytokine activity.
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PMID:Regulation of cytokine mRNAs by interferon and interferon inducers. 1268 59

Replication of human cytomegalovirus (HCMV) was investigated in various T-cell lines expressing the tax gene product of human T-cell leukemia-lymphoma virus type I (HTLV-I). Differential patterns of HCMV replication were found in HTLV-I-carrying cell lines. HCMV gene expression was restricted to the immediate-early genes in MT-2 and MT-4 cells, whereas full replication cycle of the virus was observed in C8166-45 cells. Productive HCMV infection induced a cytopathic effect resulting in the lysis of infected cells. The results of electrophoretic mobility shift assay (EMSA) showed high levels of NF-kappaB-, CREB/ATF-1-, and SRF-specific DNA binding activity in all Tax-positive cell lines. In contrast, SP1 activity could be detected only in C8166-45 cells. Using an inducible system (Jurkat cell line JPX-9), a dramatic increase in NF-kappaB, CREB/ATF-1, SRF, and SP1 binding activity, as well as productive HCMV infection, were observed upon Tax expression. Overexpression of SP1 in MT-2 and MT-4 cells converted HCMV infection from an abortive to a productive one. These data suggest that the stimulatory effect of Tax protein on HCMV in T cells is accomplished through at least five host-related transcription factor pathways. The results of this study provide possible mechanisms whereby HCMV infections might imply suppression of adult T-cell leukemia.
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PMID:Differential patterns of human cytomegalovirus gene expression in various T-cell lines carrying human T-cell leukemia-lymphoma virus type I: role of Tax-activated cellular transcription factors. 1285 14

Three new series of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases were synthesized and tested in vitro with the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine viral diarrhoea) or against drug-resistant cancers (leukaemia, carcinoma, melanoma, MDR tumors) for which no definitive cure or efficacious vaccine is available at present. In particular, these compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA(+) viruses Yellow fever virus (YFV) and Bovine viral diarrhoea virus (BVDV), both belonging to Flaviviridae. Title compounds were also tested against representatives of Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Salmonella spp.), various atypic mycobacterial strains (Mycobacterium fortuitum and Mycobacterium smegmatis), yeast (Candida albicans) and mould (Aspergillus fumigatus). None of the compounds showed antiviral or antimicrobial activity. The benzo[d]isothiazole compounds showed a marked cytotoxicity (CC(50)=4-9 microM) against the human CD4(+) lymphocytes (MT-4) that were used to support HIV-1 growth. For this reason, the most cytotoxic compounds of this series were evaluated for their antiproliferative activity against a panel of human cell lines derived from haematological and solid tumors. The results highlighted that all the benzo[d]isothiazole derivatives inhibited the growth of leukaemia cell lines, whereas only one of the above mentioned compounds (1e) showed antiproliferative activity against two solid tumor-derived cell lines.
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PMID:Synthesis and biological evaluation of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases. 1455 94

Murine fibroblasts expressing viral receptors and human cyclin T1 allow HIV-1 entry and viral gene expression but do not support efficient assembly. A chimeric HIV-1 carrying a non-homologous matrix (MA) from murine leukemia virus in place of HIV-1 MA can assemble efficiently in murine cells, yet has poor infectivity. Here, we assess the ability of a homologous MA from SIV MAC239 to complement assembly and infection in chimeric viruses designated SHIV(MA). The resulting SHIV(MA) chimeras produce more virus than native HIV-1 when transfected into murine cells. SHIV(MA) exhibits cell-type-specific replication in human T cell lines, replicating well in MT4 cells and poorly in Jurkat cells due to an incompatibility with the HIV-1 Env. The infectivity defects of SHIV(MA) are rescued by pseudotyping with VSV-G but not by truncation of the cytoplasmic tail of Env. Passage of SHIV(MA) in Jurkat cells produces variants with improved Env incorporation and improved replication in Jurkat but not in 3T3 TXC cells. The results indicate that cell-type-specific, or species-specific, host factors interact with MA to modulate the efficiency of assembly and its compatibility with Env. With additional selection, SIV/HIV-1 chimeras may be useful for the development of murine models of lentiviral infection.
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PMID:Chimeric HIV-1 containing SIV matrix exhibit enhanced assembly in murine cells and replicate in a cell-type-dependent manner in human T cells. 1656 54

A series of amino acid esters bearing coumarin (3-15) were synthesized and evaluated, in vitro, against HIV-1, and bovine viral diarrhea virus (BVDV). The in vitro cytotoxicity of 3-10 and 12 was assayed against a panel of tumor cell lines consisting of CD4 human T-cells. Compound 14 showed inhibition of HIV-1 with EC50 > 1.6 microg mL(-1), meanwhile compound 9 exhibited activity against leukaemia (MT4) with CC50 = 24 micromol L(-1).
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PMID:Amino acid derivatives. Part I. Synthesis, antiviral and antitumor evaluation of new alpha-amino acid esters bearing coumarin side chain. 1661 24

We studied antitumor effects of receptor tyrosine kinase inhibitor sunitinib (formerly SU11248) against a variety of hematologic malignancies including the following leukemias: eosinophilic (EOL-1), acute myeloid (THP-1, U937, Kasumi-1), biphenotypic (MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, PALL-2), blast crisis of chronic myeloid (KU812, Kcl-22, K562), and adult T-cell (MT-1, MT-2, MT-4), as well as non-Hodgkin's lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine uptake studies showed that sunitinib was active against EOL-1, MV4-11, and Kasumi-1 cells, which possessed activating mutations of the PDGFRalpha, FLT-3, and c-KIT genes, respectively, with IC(50)s of <30 nmol/L. In addition, sunitinib inhibited the proliferation of freshly isolated leukemia cells from patients possessing mutations in FLT3 gene. Annexin V staining showed that sunitinib induced apoptosis of these cells. Sunitinib inhibited phosphorylation of FLT3 and PDGFRalpha in conjunction with blockade of mammalian target of rapamycin signaling in MV4-11 and EOL-1 cells, respectively. Interestingly, rapamycin analogue RAD001 enhanced the ability of sunitinib to inhibit the proliferation of leukemia cells and down-regulate levels of mammalian target of rapamycin effectors p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in these cells. Taken together, sunitinib may be useful for treatment of individuals with leukemias possessing activation mutation of tyrosine kinase, and the combination of sunitinib and RAD001 represents a promising novel treatment strategy.
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PMID:The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. 1704 Oct 96

A series of 5-alkylamino and 5-alkylsulfanyl derivatives of 1-aryl-2-alkyl-4-nitro-1H-imidazoles 12-21, 31, and 34 were synthesized by a simple method with the aim to develop novel HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs). All the new compounds were tested against HIV-1 and HIV-2 in MT-4 cells. Compound 21, with an arylsulfanyl group at C(5) of the 4-nitro-1H-imidazole backbone showed an EC(50) value of 0.22 microg/ml against HIV-1 with a therapeutic index of 13. This means that compound 21 was cytotoxic to MT-4 cells at a CC(50) value of 2.57 microg/ml; also compounds 8, 22-25, 28, and 29 were cytotoxic to MT-4 cells within the 0.4-4 microg/ml concentration range. Compounds 8, and 12-21 were evaluated, as a rule, but found inactive at non-toxic concentrations against hepatitis C virus, herpes simplex type 1 and 2, cytomegalovirus (CMV), varicella-zoster virus (VZV), vaccinia virus, and vesicular stomatitis virus, and a number of other viruses. Yet, the therapeutic index of compounds 17 and 21 for CMV and VZV approached the tenfold cut-off point. Compounds 8 and 21 exhibited some cytostatic activity against leukemia and melanoma cell lines.
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PMID:Nitroimidazoles, part 2: Synthesis, antiviral and antitumor activity of new 4-nitroimidazoles. 1719 87


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