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  1. Article ; Online: Dominant negative Tax double mutants as molecular inhibitors for w.t. Tax gene functions.

    Egbaria, Mahmoud / Tabakin-Fix, Yulia / Huleihel, Mahmoud

    Leukemia research

    2009  Volume 33, Issue 7, Page(s) 974–979

    Abstract: Tax plays a key role in HTLV-1 pathogenicity, partly due to its capacity of constitutive NF-kappaB activation. Delta58Tax does not translocate to the nucleus and traps w.t. Tax molecules in the cytoplasm but still retains the cytoplasmic NF-kappaB ... ...

    Abstract Tax plays a key role in HTLV-1 pathogenicity, partly due to its capacity of constitutive NF-kappaB activation. Delta58Tax does not translocate to the nucleus and traps w.t. Tax molecules in the cytoplasm but still retains the cytoplasmic NF-kappaB activation ability. Therefore, it enhances the w.t. Tax activation of NF-kappaB when co-expressed at lower level than w.t. Tax. However, the double mutants Delta58Tax (M22) and Delta58Tax (148) are defective also in the cytoplasmic NF-kappaB activation. They were found as capable of blocking the w.t. Tax-induced NF-kappaB-dependent activation even when expressed at low levels. These double mutants may, therefore, be used as powerful tools for blocking w.t. Tax functions.
    MeSH term(s) Blotting, Western ; CREB-Binding Protein/metabolism ; Cell Nucleus/metabolism ; Cell Transformation, Viral ; Cytoplasm/metabolism ; Gene Products, tax/antagonists & inhibitors ; Gene Products, tax/genetics ; Gene Products, tax/metabolism ; Human T-lymphotropic virus 1/genetics ; Human T-lymphotropic virus 1/metabolism ; Humans ; Mutation/genetics ; NF-kappa B/metabolism ; Promoter Regions, Genetic ; Protein Transport ; Subcellular Fractions ; T-Lymphocytes/virology ; Transcription Factor RelA/metabolism ; Transcriptional Activation ; Transfection ; Tumor Cells, Cultured
    Chemical Substances Gene Products, tax ; NF-kappa B ; Transcription Factor RelA ; tax protein, Human T-lymphotrophic virus 1 ; CREB-Binding Protein (EC 2.3.1.48) ; CREBBP protein, human (EC 2.3.1.48)
    Language English
    Publishing date 2009-07
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 752396-8
    ISSN 1873-5835 ; 0145-2126
    ISSN (online) 1873-5835
    ISSN 0145-2126
    DOI 10.1016/j.leukres.2008.10.023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1321: Show issues Location:
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  2. Article: Activation of simian virus 40 promoter by HTLV-I Tax protein: role of NF-kappaB and CBP.

    Tabakin-Fix, Yulia / Huleihel, Mahmoud / Aboud, Mordechai

    Biochemical and biophysical research communications

    2004  Volume 318, Issue 4, Page(s) 1052–1056

    Abstract: HTLV-I is implicated with adult T-cell leukemia and certain other clinical disorders. The viral Tax protein is regarded as a key element in HTLV-I pathogenicity due to its ability to activate a wide variety of cellular regulatory factors. As such, Tax ... ...

    Abstract HTLV-I is implicated with adult T-cell leukemia and certain other clinical disorders. The viral Tax protein is regarded as a key element in HTLV-I pathogenicity due to its ability to activate a wide variety of cellular regulatory factors. As such, Tax may likely activate also latent infection of certain other pathogenic viruses whose expression is modulated by cellular transcription factors. Therefore, investigation of Tax effect on the expression of these viruses is of particular clinical importance, since HTLV-I infection of carriers harboring such latent viruses may trigger their related diseases. In this study we focused on simian virus 40 and demonstrated that Tax activates the promoter of this virus through NF-kappaB-associated pathway. Furthermore, we show that this activation requires an interaction of the NF-kappaB factor p65(RelA) with CBP, which depends on PKA-mediated phosphorylation of p65(RelA). Finally, the present study proves that the nuclear Tax plays a critical role in Tax-induced NF-kappaB-mediated SV40 activation.
    MeSH term(s) CREB-Binding Protein ; Cell Nucleus/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Gene Expression ; Gene Products, tax/genetics ; Gene Products, tax/metabolism ; Humans ; Jurkat Cells ; NF-kappa B/metabolism ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic/genetics ; Simian virus 40/genetics ; Trans-Activators/metabolism ; Transcription Factor RelA ; Transfection ; beta-Galactosidase/genetics ; beta-Galactosidase/metabolism
    Chemical Substances Gene Products, tax ; NF-kappa B ; Nuclear Proteins ; Trans-Activators ; Transcription Factor RelA ; CREB-Binding Protein (EC 2.3.1.48) ; CREBBP protein, human (EC 2.3.1.48) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; beta-Galactosidase (EC 3.2.1.23)
    Language English
    Publishing date 2004-06-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 205723-2
    ISSN 0006-291X ; 0006-291X
    ISSN (online) 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2004.04.137
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: HTLV-1 tax-induced NF-kappaB activation is synergistically enhanced by 12-O-tetradecanoylphorbol-13-acetate: mechanism and implications for Tax oncogenicity.

    Azran-Shaish, Inbal / Tabakin-Fix, Yulia / Huleihel, Mahmoud / Bakhanashvili, Mary / Aboud, Mordechai

    Journal of molecular medicine (Berlin, Germany)

    2008  Volume 86, Issue 7, Page(s) 799–814

    Abstract: Nuclear factor kappa B (NF-kappaB) factors regulate a wide range of physiological and oncogenic processes. Normally, these factors are transiently activated by specific external signals which induce their dissociation from inhibitors of kappaB (IkappaB) ... ...

    Abstract Nuclear factor kappa B (NF-kappaB) factors regulate a wide range of physiological and oncogenic processes. Normally, these factors are transiently activated by specific external signals which induce their dissociation from inhibitors of kappaB (IkappaB) and subsequent translocation to the nucleus where p65 links to the cyclic adenosine monophosphate response element binding protein (CBP)-p300 and P/CAF coactivators that are essential for its transcriptional activity. The pathogenic potential of human T-cell leukemia virus type 1 (HTLV-1) Tax protein is partly ascribed to its capacity to constitutively activate NF-kappaB factors because constitutive activity of these factors play an important role in the pathophysiology of adult T-cell leukemia (ATL) and tropical spastic paraparesis-HTLV-1 associated myelopathy (TSP-HAM). In assessing the possibility of modulating Tax pathogenic potential by external factors, we focused here on 12-O -tetradecanoylphorbol-13-acetate (TPA) which is a potent protein kinase C (PKC) activator. There are conflicting reports regarding the effect of TPA and PKC on NF-kappaB. Therefore, we reassessed this issue and also investigated their influence on Tax-mediated activation of these factors. We found that TPA promoted NF-kappaB nuclear translocation and the DNA binding of p65 dimers through PKC activation. However, both TPA and ectopically expressed PKC had only a marginal effect on the transcriptional competence of these dimers, indicating that the DNA binding of such dimers is insufficient by itself for gene activation. Notably, however, both TPA and the ectopic PKC displayed strong synergistic enhancement of the Tax-induced activation of the NF-kappaB transcriptional function. In contrast, TPA and the ectopic PKC only slightly elevated the low activation of the NF-kappaB transcriptional capacity by cytoplasmic Tax mutants, indicating that the nuclear translocation of Tax was essential for this synergism. Subsequent experiments suggested that TPA contributed to this synergism by increasing the pool of free p65 which Tax could link to CBP and elevate, thereby, the amount of a p65-Tax-CBP ternary complex that could bind to NF-kappaB-responsive promoters and stimulate their expression. Finally, we demonstrated that this synergism operated also in HTLV-1-infected human T-cells. Earlier reports have shown a close linkage of pathological PKC-activating conditions (e.g., infectious and inflammatory diseases) to certain malignancies. On this ground, the present study suggests that such conditions may enhance the risk for ATL and TSP-HAM in HTLV-1 carriers by increasing the Tax-induced NF-kappaB activation.
    MeSH term(s) Base Sequence ; CREB-Binding Protein/metabolism ; Carcinogens/pharmacology ; Cell Line ; Cytoplasm/metabolism ; Gene Products, tax/genetics ; Gene Products, tax/metabolism ; Human T-lymphotropic virus 1/metabolism ; Humans ; Jurkat Cells ; Leukemia, T-Cell/metabolism ; Molecular Sequence Data ; Mutation ; NF-kappa B/metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Transfection
    Chemical Substances Carcinogens ; Gene Products, tax ; NF-kappa B ; tax protein, Human T-lymphotrophic virus 1 ; CREB-Binding Protein (EC 2.3.1.48) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
    Language English
    Publishing date 2008-04-19
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1223802-8
    ISSN 1432-1440 ; 0946-2716
    ISSN (online) 1432-1440
    ISSN 0946-2716
    DOI 10.1007/s00109-008-0335-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Functional inactivation of p53 by human T-cell leukemia virus type 1 Tax protein: mechanisms and clinical implications.

    Tabakin-Fix, Yulia / Azran, Inbal / Schavinky-Khrapunsky, Yana / Levy, Oren / Aboud, Mordechai

    Carcinogenesis

    2006  Volume 27, Issue 4, Page(s) 673–681

    Abstract: Human T-cell leukemia virus type 1 (HTLV-I) has been implicated with the etiology of adult T-cell leukemia (ATL) and certain other clinical disorders. Although the leukemogenic mechanism of HTLV-1 is not fully understood yet, the viral Tax protein is ... ...

    Abstract Human T-cell leukemia virus type 1 (HTLV-I) has been implicated with the etiology of adult T-cell leukemia (ATL) and certain other clinical disorders. Although the leukemogenic mechanism of HTLV-1 is not fully understood yet, the viral Tax protein is widely regarded as a key factor in this mechanism. Tax can modulate the synthesis or function of many regulatory factors which control a wide range of normal and oncogenic cellular processes and therefore, it acts as a potent oncoprotein. In the last few years, special attention has been attracted to Tax interference with the transactivation function of p53, a tumor-suppressor protein that is involved in regulation of the cell-cycle and apoptosis and in maintaining the cellular genome integrity. p53 is mutated in approximately 60% of all human tumors. In contrast, mutant p53 is found in only small percentage of ATL patients. Nevertheless, p53 is inactive in the leukemic cells of most ATL patients and in most HTLV-1 transformed cells. By inactivating p53, Tax can immortalize the HTLV-1-infected cells and destabilize their genome. Consequently, such cells can progress toward the ultimate leukemic state by a stepwise accumulation of oncogenic mutations and other types of chromosomal aberrations. Furthermore, since p53 exists in most ATL patients in its wild-type form, its reactivation by therapeutic drugs might be an effective approach for ATL therapy. Several mechanisms have been proposed so far for Tax-induced p53 inactivation. Understanding the exact mechanism of this Tax effect is essential for designing effective means for this therapeutic approach. In this review article, we discuss the various mechanisms proposed for Tax interference with p53 functions and their clinical and therapeutic implications.
    MeSH term(s) Cell Transformation, Neoplastic/genetics ; DNA Mutational Analysis ; Gene Expression Regulation, Neoplastic ; Gene Products, tax/physiology ; Genes, p53 ; Humans ; Leukemia-Lymphoma, Adult T-Cell/genetics ; Leukemia-Lymphoma, Adult T-Cell/virology ; Transcriptional Activation ; Tumor Suppressor Protein p53/biosynthesis ; Tumor Suppressor Protein p53/physiology
    Chemical Substances Gene Products, tax ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2006-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 603134-1
    ISSN 1460-2180 ; 0143-3334
    ISSN (online) 1460-2180
    ISSN 0143-3334
    DOI 10.1093/carcin/bgi274
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1558: Show issues Location:
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