Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human lymphotropic virus, HTLV-1, encodes in its proviral genome a transcriptional activator protein, tax-1, that may be responsible for the development of virus-induced adult T cell leukemia (ATL), possibly through the aberrant activation of the genes for interleukin-2 (IL-2) and one of its receptor (IL-2R) components, the IL-2 receptor alpha-chain (IL-2R alpha). In the present study, an expression plasmid containing tax-1 cDNA under the control of HTLV-1 LTR was introduced into mouse and human CD4-positive T cell lines. Analysis of the established cell clones revealed a number of interesting features: (i) a limited fraction of the total cell population (less than 25% in each clone) was positive for IL-2R alpha; (ii) the IL-2R alpha expression was not permanent, as the IL-2R alpha positive and negative cells could convert either way. The experimental data suggest that the observed heterogeneity in IL-2R alpha expression in the transformants is due to a cell-cycle-regulated expression and function of tax-1. Furthermore, a proportion of the induced IL-2R in EL-4 was in high-affinity form, suggesting the association of the IL-2R alpha and the IL-2R beta chain (p70-75) components.
 ...
PMID:Transient induction of IL-2 receptor in cultured T cell lines by HTLV-1 LTR-linked tax-1 gene. 279 77

The viral oncogene Tax derived from human T cell leukemia virus type I (HTLV-I) is a positive transcriptional activator of HTLV-1 gene expression. Tax is also able to indirectly stimulate transcription of several growth regulatory genes by an indirect mechanism via association with host transcription factors. One of the cellular targets of the trans-activating effects of Tax is the NF-kappa B/Rel family transcription factors, pleiotropic regulators of immunoregulatory, cytokine, and viral gene expression. Recent studies demonstrated that specific subunits of NF-kappa B (NFKB2(p 100) and c-Rel) were overexpressed in HTLV-I-infected and Tax-expressing cells. Furthermore, Tax physically associated with NFKB2(p 100). Monospecific antibodies directed against individual NF-kappa B subunits were generated and used to investigate the consequences of the interactions between Tax and NF-kappa B in a cotransfection-immunofluorescence assay. These studies demonstrate: (1) distinct compartmentalization of NF-kappa B precursors and products, (2) differential induction of the endogenous I kappa B alpha protein by transfected NF-kappa B subunits, (3) subcellular relocalization of Tax to the cytoplasm or nucleus depending on the coexpressed NF-kappa B subunit, and (4) Tax interaction with the Rel homology domain region of NFKB2. These studies indicate that the transcription modulatory influence of HTLV-I Tax may be significantly influenced by cytoplasmic-nuclear partitioning associated with the NF-kappa B proteins.
 ...
PMID:Subcellular redistribution of HTLV-1 Tax protein by NF-kappa B/Rel transcription factors. 794 39

Molecular, biochemical and epidemiological evidence implicate HTLV-I as an etiologic agent of adult T cell leukemia (ATL). The Tax protein of HTLV-I, a positive transcriptional activator of HTLV-I gene expression, is a viral oncogene that also increases transcription of cellular genes including GM-CSF, IL-2R alpha and IL-2. One of the cellular targets of the trans-activating effects of Tax is the NF-kappa B/Rel family of transcription factors, pleiotropic regulators of immunoregulatory, cytokine and viral gene expression. In this report, we demonstrate that NFKB2 (lyt-10) and c-Rel are overexpressed in HTLV-I infected and Tax-expressing cells and, together, account for the majority of the constitutive NF-kappa B binding activity in these cells before and after PMA stimulation. Most importantly, we show a Tax-dependent correlation between expression of NFKB2(p100) and processing to the DNA binding NFKB2(p52) form, induction of c-Rel, and trans-activation of NF-kappa B-mediated gene expression. Furthermore, the NFKB2 precursor is physically associated with c-Rel and with Tax in HTLV-I infected cells. We propose that NFKB2 synthesis and processing allows continuous nuclear expression of an otherwise cytoplasmic protein and, in conjunction with overexpression of c-Rel, NFKB2 alters the NF-kappa B signalling pathway and contributes to leukemic transformation of T cells by HTLV-I.
 ...
PMID:Overproduction of NFKB2 (lyt-10) and c-Rel: a mechanism for HTLV-I Tax-mediated trans-activation via the NF-kappa B signalling pathway. 810 27

Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia/lymphoma (ATLL). HTLV Tax, the viral transcriptional activator, can activate a variety of cellular genes. HTLV-mediated T-cell transformation, however, may involve additional viral proteins expressed from singly- as well as doubly-spliced viral mRNA. To determine the combined effect of these viral proteins on cellular gene expression in Jurkat T-cells, we derived stable transfectants that constitutively express the HTLV-I pX and env regions (J3.9). J3.9 cells show substantially increased mRNA levels of egr-1 and c-jun but no induction of either CD25 or GM-CSF by Northern blotting. This pattern corresponded to the activation of an egr-1 but not a GM-CSF promoter-driven reporter construct in transient gene expression assays. In DNA electrophoretic mobility shift assays (EMSA), nuclear extract from J3.9 cells has significantly increased binding to CRE and SRE but not nuclear factor kappa B (NF kappa B) DNA oligos, as compared to J-Neo cell extract. These results suggest that low level expression of pX and env region gene products in Jurkat T-cells stimulates persistent activation of CRE- and SRE- but not NF kappa B-induced cellular genes.
 ...
PMID:Constitutive expression of the HTLV-I pX and env regions in Jurkat T-cells induces differential activation of SRE, CRE and NF kappa B pathways. 942 75

Biological, molecular, and epidemiological data have demonstrated that human T cell leukemia virus type 1 (HTLV-1) encoded Tax protein plays a central role in the initiation of T cell malignancy. The 40-kDa Tax oncoprotein serves as a potent transcriptional activator that induces viral gene expression driven by the HTLV-1 long terminal repeats and also stimulates multiple cellular genes involved in T cell activation, cell cycle regulation, and gene activation. Since Tax has been shown to interact directly and indirectly with the NF-kappa B/I kappa B regulatory proteins, we examined the significance of an in vivo association between Tax and the I kappa B alpha inhibitor. Using GST affinity chromatography, Tax was shown to interact with the I kappa B alpha ankyrin repeats which are essential for interaction with the NF-kappa B/Rel proteins. In vivo, using I kappa B alpha mutants and co-immunoprecipitation, a preferential interaction between HTLV-1 Tax and N-terminally hypophosphorylated I kappa B alpha was detected. Tax also enhanced binding of I kappa B alpha to the proteasome subunit HsN3, resulting in a Tax-enhanced, constitutive degradation of wild-type and mutated forms of I kappa B alpha in the absence of phosphorylation and ubiquitination. Binding of I kappa B alpha to proteasome subunit HC9 was also observed, but this interaction occurred independently of Tax. Taken together, these results suggest a role for Tax as a viral chaperone resulting in the enhanced constitutive turnover of I kappa B alpha. The association of Tax with hypophosphorylated I kappa B alpha may prevent I kappa B alpha from binding to NF-kappa B and also target I kappa B alpha to the proteasome for degradation via a phosphorylation-independent pathway.
 ...
PMID:Association between HTLV-1 Tax and I kappa B alpha is dependent on the I kappa B alpha phosphorylation state. 987 28

Adult T-cell leukemia (ATL) is a malignancy of mature T cells that is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1). The frequent manifestation of ATL is infiltration of leukemic cells into various organs. Besides certain cell adhesion molecules and matrix metalloproteineses, chemokine receptors may play important roles in tissue infiltration of ATL. Identification of a unique set of chemokine receptors expressed by ATL would thus provide valuable information about the molecular mechanism of tissue infiltration of ATL. This may also reveal that ATL frequently develops from a certain subset of T cells that express a particular set of chemokine receptors. Since HTLV-1 encodes a potent viral transcriptional activator Tax, which is known to induce various cellular genes, expression of some chemokine receptors may be affected by Tax. This, however, may relate more to HTLV-1-infected T cells, since ATL cells usually do not express Tax. Finally, identification of a unique set of chemokine receptors expressed by ATL may also provide a new therapeutic target. These considerations prompted us to examine the chemokine receptor expression in ATL. We found that in the majority of ATL cases, leukemic cells consistently express CCR4. Since CCR4 is known to be involved in T cell migration into skin, this may in part explain the frequent skin infiltration in ATL. Furthermore, CCR4 is known to be selectively expressed by Th2 and regulatory T cells. Thus, the majority of ATL may predominantly originate from either Th2 or regulatory T cells.
 ...
PMID:Expression of CCR4 in adult T-cell leukemia. 1562

The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4+ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30II/Myc-TIP60 chromatin-remodeling complexes. The p30II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30II interact with the TIP60 HAT, and p30II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.
 ...
PMID:A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions. 1598 28

Human T cell leukemia virus type 1 (HTLV-1) is a complex human retrovirus which is the causative agent of adult T cell leukemia (ATL). ATL occurs in about 4% of carriers and develops after a long latent period. Although the precise mechanism of HTLV-1 oncogenesis remains unclear, the pathogenesis has been linked to the pleiotropic activity of the viral transcriptional activator protein Tax. Tax has been shown to regulate viral and cellular gene expression and to functionally interfere with proteins involved in cell-cycle progression and DNA repair. This review will focus on the role of Tax in p53 inhibition.
 ...
PMID:Human T cell leukemia virus type 1: the role of Tax in leukemogenesis. 1608 13

Adult T-cell leukemia (ATL) is a highly aggressive mature CD4+ T-cell malignancy that is etiologically associated with human T-lymphotropic virus Type 1 (HTLV-1). ATL is characterized by frequent infiltration of lymph nodes, spleen, liver, skin and gut. Previously, we and others have shown that the majority of ATL cases are strongly positive for CCR4, which may explain the frequent skin invasion of ATL. Here, we examined whether ATL cells express CCR9, which is involved in T-cell homing to the gastrointestinal tract. Human T cell lines carrying HTLV-1 consistently expressed CCR9 together with the HTLV-1-encoded transcriptional activator Tax. Although ATL cells freshly isolated from peripheral blood hardly expressed CCR9, ATL cells cultured for 1 day consistently expressed CCR9 in parallel with the upregulation of Tax. Induction of Tax by Cd2+ in JPX-9, a subline of Jurkat human T cell line carrying Tax under the control of metallothionein promoter, led to upregulation of CCR9. A luciferase reporter gene under the control of the CCR9 promoter was expressed by cotransfection of an expression vector for Tax or in Cd2+-treated JPX-9 cells. Furthermore, immunohistochemical staining demonstrated that ATL cells infiltrating gastrointestinal tract were frequently positive for CCR9. Collectively, CCR9 is inducible in ATL cells expressing Tax and may play a role in the gastrointestinal involvement of ATL.
 ...
PMID:Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax. 1720 12

HTLV-I infection is associated with the development of adult T cell leukemia (ATL) and the neuroinflammatory disease HAM/TSP. There are quantitative and qualitative differences in the antiviral cytotoxic T cell (CTL) response in ATL and HAM/TSP although the underlying mechanisms are unclear. Here, we demonstrate that the HTLV-I Tax trans-activating protein is a transcriptional activator of CD40 ligand (CD40L), a critical regulator of dendritic cell maturation and adaptive immunity. Tax activates CD40L expression via a cyclosporin A insensitive pathway that is also independent of NF-kappaB. Although Tax upregulates CD40L gene expression, CD40L expression is absent in Tax-expressing HTLV-I-transformed cell lines via an epigenetic mechanism involving methylation. T lymphocytes cultured ex vivo from ATL patients, but not HAM/TSP or normal controls, exhibit a potent block in the induction of CD40L, but not CD69. However, the CD40L gene is not silenced by methylation in ATL patients, thus CD40L is downregulated by distinct mechanisms in HTLV-I-transformed cell lines and ATL patients.
 ...
PMID:Deregulated expression of CD40 ligand in HTLV-I infection: distinct mechanisms of downregulation in HTLV-I-transformed cell lines and ATL patients. 1725 59


1 2 Next >>