Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Human T-cell leukemia virus type I (HTLV-I) Rex and human immunodeficiency virus type 1 (HIV-1) Rev are essential gene products required for the replication of these two pathogenic human retroviruses. Both Rex and Rev act at a posttranscriptional level by binding to highly structured RNA-response elements, the Rex-response element in HTLV-I and the Rev-response element in HIV-1. Using a sensitive in vivo assay of protein-protein interaction, we now demonstrate that the HTLV-I Rex and HIV-1 Rev proteins readily form homomultimeric complexes in the absence of their cognate RNA-response elements yet fail to form heteromultimeric complexes with each other. Dominant negative mutations have been identified in both the rex and rev genes which presumably specify a critical activation or effector domain in each of these viral transactivators. Surprisingly, these dominant negative mutants of Rex and Rev fail to interact in vivo. These findings raise the possibility that the binding of nonfunctional monomers rather than functional multimers underlies the transdominant phenotype of these Rex and Rev mutants. Further, it seems likely that the assembly of functional and stable multimers of Rex and Rev in vivo may depend not only on the intrinsic multimerization domains of these proteins but also on the binding of a bridging cellular cofactor to the related activation domains present in each viral transactivator.
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PMID:Dominant negative mutants of human T-cell leukemia virus type I Rex and human immunodeficiency virus type 1 Rev fail to multimerize in vivo. 847 55

All-trans retinoic acid (ATRA) is successfully used in the cyto-differentiating treatment of acute promyelocytic leukemia (APL). Paradoxically, APL cells express PML-RAR, an aberrant form of the retinoic acid receptor type alpha (RAR alpha) derived from the leukemia-specific t(15;17) chromosomal translocation. We show here that AM580, a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts. After treatment of APL cells with AM580 either alone or in combination with granulocyte colony-stimulating factor (G-CSF), the compound induces granulocytic maturation, as assessed by determination of the levels of leukocyte alkaline phosphatase, CD11b, CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects. By contrast, AM580 is not effective as ATRA in modulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease. In NB4 cells, two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally ineffective. These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which PML-RAR is present. Binding experiments, using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha, show that AM580 has a lower affinity than ATRA for both receptors. However, in the presence of PML-RAR, the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoid, whereas, in the presence of RAR alpha, AM580 and ATRA have similar activity. This may explain the strong cyto-differentiating potential of AM580 in PML-RAR-containing leukemic cells.
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PMID:AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells. 860 43

Human T cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T cell leukemia (ATL) transforms human T cells in vitro and in vivo. Tax, the major transactivator of HTLV-I is critical for the initial events involved in transformation, however, the later steps required for progression from an IL-2 dependent state to one of IL-2 independence remain to be clarified. We investigated the potential role of p53 protein in this process employing several IL-2 dependent and independent HTLV-I transformed cell lines. All cell lines examined were found to be wild-type in the p53 coding region usually associated with inactivating mutations using RT-PCR-SSCP analysis and DNA sequencing. Levels of p53 protein were consistently higher in IL-2 independent lines compared to IL-2 dependent ones. Lack of functional p53 activity was observed only in IL-2 independent cell lines using a transfection assay with a B-galactosidase reporter gene construct responsive to wild-type p53 protein. Increased steady state levels of wild-type p53 protein associated with its functional inactivation appear to be linked to the loss of IL-2 dependent growth in HTLV-I transformed lymphocytes.
Leukemia 1995 Dec
PMID:Functional inactivation of wild-type p53 protein correlates with loss of IL-2 dependence in HTLV-I transformed human T lymphocytes. 860 20

The HBx protein is a small polypeptide encoded by mammalian hepadnaviruses that is essential for viral infectivity and is thought to play a role in development of hepatocellular carcinoma during chronic hepatitis B virus infection. HBx is a transactivator that stimulates Ras signal transduction pathways in the cytoplasm and certain transcription elements in the nucleus. To better understand the activities of HBx protein and its mechanism of action, we have explored the manner by which HBx activates the transcription factor NF-kappaB during transient expression. We show that HBx induces prolonged formation, in a Ras-dependent manner, of transcriptionally active NF-kappaB DNA-binding complexes, which make up the family of Rel-related proteins, p50, p52, RelA, and c-Rel. HBx was found to activate NF-kappaB through two distinct cytoplasmic pathways by acting on both the 37-kDa IkappaBalpha inhibitor and the 105-kappaDa NF-kappaB1 precursor inhibitor protein, known as p105. HBx induces phosphorylation of IkappaBalpha, a three- to fourfold reduction in IKBalpha stability, and concomitant nuclear accumulation of NF-kappaB DNA-binding complexes, similar to that reported for human T-cell leukemia virus type 1 Tax protein. In addition, HBx mediates a striking reduction in cytoplasmic p105 NF-kappaB1 inhibitor and p50 protein levels and release of RelA protein that was sequestered by the p105 inhibitor, concomitant with nuclear accumulation of NF-kappaB complexes. HBx mediated only a slight reduction in the cytoplasmic levels of NF-kappaB2 p100 protein, an additional precursor inhibitor of NF-kappaB, which is thought to be less efficiently processed or less responsive to release of NF-kappaB. No evidence was found for HBx activation of NF-kappaB by targeting acidic sphingomyelinase- controlled pathways. Studies also suggest that stimulation of NF-kappaB by HBx does not involve activation of Ras via the neutral sphingomyelin-ceramide pathway. Thus, HBx protein is shown to activate the NF-kappaB family of Rel-related proteins by acting on two distinct NF-kappaB cytoplasmic inhibitors.
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PMID:Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of rel-related proteins. 867 82

Human T cell leukemia virus type I (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy, also called tropical spastic paraparesis (HAM/TSP). Both clinical and in vitro evidence have demonstrated that the virus or its transactivator Tax, are transforming. However, transformation appears to require additional, as yet poorly characterized, genetic changes in infected cells. JNK is a recently characterized member of the MAP kinase family. Its signaling cascade is distinct from other members and has been demonstrated to play an important role in T-cell activation, at least partially through its downstream targets, c-jun and ATF-2. Here we demonstrate constitutive activation of the JNK cascade in human lymphocytes transformed in vitro by HTLV-1 and also in Tax transformed murine fibroblasts. Such activation is not induced by Tax expression alone, and occurs only when infected lymphocytes become IL-2 independent or immortalized. Constitutive JNK activation was also found in leukocytes isolated from ATL patients. The acquisition of constitutive JNK activation may represent an important later event in HTLV-1 tumorigenesis.
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PMID:Constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis. 870 May 39

We studied the serum levels of interleukin-10 (IL-10), in patients with adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) infection. Elevated IL-10 levels were observed in 33 of 45 patients with ATL. Fresh leukemic cells from ATL patients as well as HTLV-I-infected T-cell lines MT-2, SLB-1, and C10/MJ expressed IL-10 mRNA by reverse transcription-polymerase chain reaction analysis, whereas IL-10 mRNA was not detected in normal peripheral mononuclear cells and an uninfected T-cell line Jurkat. IL-10 protein was also detected in the culture medium of leukemic cells from ATL patients as well as these HTLV-I-infected cell lines, and in the extracellular fluids of ATL patients. Interestingly, MT-4 cells, which did not express Tax although transformed by HTLV-I, did not express IL-10 at either the mRNA or protein level. To elucidate the role of the HTLV-I encoded transactivator Tax in IL-10 gene expression, Jurkat cells were transfected with a Tax expression plasmid. In transiently transfected Jurkat cells, endogenous IL-10 mRNA expression was induced by Tax. Stably transfected Jurkat cell lines expressed IL-10 mRNA and secreted IL-10 protein into the culture medium. The nuclear factor (NF)-kappa B pathway is a target for Tax transactivation. We treated MT-2 cells with phosphorothioate antisense oligonucleotides to the p65 subunit of NF-kappa B. A reduction in the expression of p65 was accompanied by a reduction in IL-10 gene expression and IL-10 production. We showed that the IL-10 kappa B-like sites ( kappa B1,-2,034 to -2,025; kappa B2, -1,961 to -1,952; kappa B3, -452 to -443) specifically formed a complex with NF-kappa B-containing nuclear extract from MT-2 cells and that NF-kappa B bound with the highest affinity to the kappa B2 element (kappa B2 > kappa B3 > kappa B1). These data suggest a general role for NF-kappa B activation in the induction of IL-10 gene transcription. Activation of IL-10 in HTLV-I-infected cells may contribute to the pathology associated with HTLV-I infection.
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PMID:Interleukin-10 gene expression in adult T-cell leukemia. 870 12

Interactions between the Tax transactivator of human T-cell leukemia virus type 1 (HTLV-1) and a cell cycle regulatory protein have been examined. We report cooperative stimulation of human immunodeficiency virus type 1 gene expression by Tax and a regulator of cell cycle progression, the p21 cyclin-dependent kinase inhibitor (CKI). This cooperativity results from the effect of p21 on transcriptional coactivation by Tax-induced NF-kappaB. This effect was abrogated by a mutation in Tax which specifically eliminated NF-kappaB induction, was inhibitable by IkappaB-alpha, and was markedly reduced in human immunodeficiency virus reporter plasmids with mutant kappaB sites. These studies demonstrate that transcriptional activation by Tax is influenced by cell cycle regulatory proteins.
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PMID:A cooperative interaction of human T-cell leukemia virus type 1 Tax with the p21 cyclin-dependent kinase inhibitor activates the human immunodeficiency virus type 1 enhancer. 876 97

We have generated a human 293-derived retroviral packaging cell line (293GPG) capable of producing high titers of recombinant Moloney murine leukemia virus particles that have incorporated the vesicular stomatitis virus G (VSV-G) protein. To achieve expression of the retroviral gag-pol polyprotein, the precise coding sequences for gag-pol were introduced into a vector which utilizes totally nonretroviral signals for gene expression. Because constitutive expression of the VSV-G protein is toxic in 293 cells, we used the tetR/VP 16 transactivator and teto minimal promoter system for inducible, tetracycline-regulatable expression of VSV-G. After stable transfection of the 293GPG packaging cell line with the MFG.SnlsLacZ retroviral vector construct, it was possible to readily isolate stable virus-producing cell lines with titers approaching 10(7) colony-forming units/ml. Transient transfection of 293GPG cells using a modified version of MFG.SnlsLacZ, in which the cytomegalovirus IE promoter was used to drive transcription of the proviral genome, led to titers of approximately 10(6) colony-forming units/ml. The retroviral/VSV-G pseudotypes generated using 293GPG cells were significantly more resistant to human complement than commonly used amphotropic vectors and could be highly concentrated (> 1000-fold). This new packaging cell line may prove to be particularly useful for assessing the potential use of retroviral vectors for direct in vivo gene transfer. The design of the cell line also provides at least theoretical advantages over existing cell lines with regard to the possible release of replication-competent virus.
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PMID:A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. 887 47

Human T cell leukemia virus type 1 (HTLV-1) encodes a strong transcriptional transactivator, the Tax protein, that stimulates viral transcription through the long terminal repeat and also stimulates many cellular genes via the activation of host transcription factors. Previous studies have demonstrated that Tax activates NF-kappa B through binding to the Rel homology domain of NF-kappa B proteins. Tax was also shown to increase degradation of I kappa B alpha resulting in the induction of NF-kappa B DNA binding activity. We addressed the specificity and function of Tax interaction with members of the NF-kappa B/I kappa B alpha family by using EMSA, protein affinity chromatography, protein-protein crosslinking and co-immunoprecipitation assays. The results of the present study demonstrate that: (1) Tax enhances NF-kappa B binding to DNA 40- to 100-fold by increasing NF-kappa B dimer formation which can be detected in the absence of DNA; (2) Tax binds to all NF-kappa B DNA binding subunits in vitro and to I kappa B alpha; (3) Tax physically associates with I kappa B alpha in vivo; and (4) Tax and I kappa B alpha have antagonistic effects on NF-kappa B binding and gene activity. These results suggest that Tax interaction with I kappa B alpha interferes with the formation of NF-kappa B-I kappa B alpha complexes and may play a role in targeting I kappa B alpha for degradation.
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PMID:Human T cell leukemia virus type 1 tax protein increases NF-kappa B dimer formation and antagonizes the inhibitory activity of the I kappa B alpha regulatory protein. 891 33

The expression of c-ets2 is rapidly induced in a variety of myelomonocytic cell lines as they differentiate into macrophages. We find that constitutive expression of c-ets2 in the M1D+ myeloblast leukemic cell line (M1ets2) is sufficient to push these cells to a more differentiated state. The expression of several differentiation-specific genes is upregulated in M1ets2 cells, including those encoding macrophage-specific lysozyme M and tumor necrosis factor alpha, which are involved in bacteriolytic and inflammatory processes, respectively. Transcription factors c-jun and junB, previously shown to induce partial macrophage differentiation when overexpressed in myelomonocytic leukemia cell lines, are also upregulated in M1ets2 cells. The upregulation of junB is the result of a direct interaction of Ets2 with ets binding sites of the junB promoter, since transient or constitutive Ets2 expression in M1D+ cells activates junB transcription via ets binding sites. In addition, transfection of a dominant negative mutant of Ets2, devoid of its transcriptional activation domain, greatly reduces transcriptional activities of the junB promoter in M1ets2 cells. Finally, unlike their parental M1D+ counterparts, M1ets2 cells secrete the macrophage colony-stimulating factor, CSF-1, and are able to phagocytize. Taken together, these results show that when the immature myeloid M1D+ cell line constitutively expresses c-ets2, these cells acquire different functions of mature macrophages.
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PMID:Constitutive c-ets2 expression in M1D+ myeloblast leukemic cells induces their differentiation to macrophages. 894 40


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