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 T cell leukemia virus type 1 (HTLV-I) is the etiologic agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) with an autoimmune condition. We examined the sensitivity of HTLV-I-infected T cell lines to Fas-mediated apoptosis, which plays a critical role in the elimination of self-reactive T cells. Among 13 human T-cell lines, all 4 HAM-derived T cell lines and 4 of 6 non-HAM/HTLV-I T cell lines were resistant to apoptosis induced by anti-Fas antibody, whereas only 1 of 3 uninfected cell lines was resistant to apoptosis. The cell lines resistant to apoptosis expressed the viral tax gene and/or the cellular FAP-1 (Fas-associated phosphatase) gene, both of which inhibit Fas-mediated apoptosis in T cell lines. Although Tax is a transcriptional activator of a number of cellular genes, the expression of Tax in a T cell line did not induce the expression of FAP-1, suggesting that these two antiapoptotic proteins independently function in HTLV-I-infected cells. Seven of 10 HTLV-I-infected cell lines, compared with only 1 of 3 virus-negative cell lines, expressed FAP-1. All four HAM cell lines expressed the FAP-1 gene, and its level in these cells was higher than in other T cell lines. Our results suggest that virus-infected T cells escape Fas-mediated immune surveillance by the function of Tax and FAP-1, and this escape may be involved in the autoimmune condition observed in HAM/TSP patients.
 ...
PMID:Expression of FAP-1 (Fas-associated phosphatase) and resistance to Fas-mediated apoptosis in T cell lines derived from human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patients. 949 17

Human T-cell leukemia virus type I (HTLV-I) is the etiological agent for adult T-cell leukemia (ATL), as well as for tropical spastic paraparesis (TSP) and HTLV-I associate myelopathy (HAM). A biological understanding of the involvement of HTLV-I and in ATL has focused significantly on the workings of the virally-encoded 40 kDa phospho-oncoprotein, Tax. Tax is a transcriptional activator. Its ability to modulate the expression and function of many cellular genes has been reasoned to be a major contributory mechanism explaining HTLV-I-mediated transformation of cells. In activating cellular gene expression, Tax impinges upon several cellular signal-transduction pathways, including those for CREB/ATF and NF-kappa B. In this paper, we review aspects of Tax's transcriptional potential with particular focus on recent evidence linking Tax to IKK (I kappa B-kinase)-complex and MAP3Ks (mitogen-activated protein kinase kinase kinases).
 ...
PMID:Functional activities of the human T-cell leukemia virus type I Tax oncoprotein: cellular signaling through NF-kappa B. 1132 3

HTLV-I is the etiologic agent of ATL and of tropical spastic paraparesis/HTLV-I-associated myelopathy. Infiltration of various tissues by circulating leukemic cells and HTLV-I-infected T cells is a characteristic of ATL and HTLV-I-associated inflammatory diseases. Chemokines play important roles in migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCL5 (RANTES) in ATL and HTLV-I-infected T-cell lines. Among various human T-cell lines, those infected with HTLV-I selectively expressed the CCL5 gene and secreted CCL5. Furthermore, CCL5 was expressed by leukemic cells in peripheral blood and lymph nodes from patients with ATL. Inducible expression of HTLV-I transcriptional activator Tax in a human T-cell line Jurkat, up-regulated CCL5 mRNA and induced CCL5 secretion. Analysis of the CCL5 promoter revealed that this gene is activated by Tax, via the activation of NF-kappaB, whose responsive element, R(A/B), is located at positions -71 to -43 relative to the putative transcription start site. Aberrant expression of CCL5 by HTLV-I-infected T cells may impact on the pathophysiology of HTLV-I-associated diseases.
 ...
PMID:Elevated expression of CCL5/RANTES in adult T-cell leukemia cells: possible transactivation of the CCL5 gene by human T-cell leukemia virus type I tax. 1523 33

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). 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 concentrate on the ability of Tax to promote cellular proliferation through activation of the NF-kappaB pathway while inhibiting the cell-cycle checkpoint and apoptotic function of the tumor suppressor gene p53.
 ...
PMID:Setting the stage for transformation: HTLV-1 Tax inhibition of p53 function. 1556 30

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of both adult T-cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the genesis of HAM/TSP likely involves several steps, the generation of a highly specific and effective population of Tax-specific CD8+ cytotoxic T lymphocytes (CTLs) that migrate to the central nervous system (CNS) is of pivotal importance in this neuropathologic process. Presentation of Tax peptides by activated dendritic cells (DCs) to naive CD8+ T cells likely plays an important role in the induction of a Tax-specific CTL response and the eventual neurologic dysfunction observed in HAM/TSP. The immune response mounted during HTLV-I infection is primarily targeted against Tax with both Tax-specific antibodies and CTLs found in HTLV-I-infected individuals, indicating that Tax is available for immune recognition. Studies have suggested that Tax may be secreted from HTLV-I-infected cells and act as an extracellular cytokine, be internalized and processed for presentation, or be transported to the nucleus where it may act as a transcriptional activator. The authors report in this article that purified Tax induces DC activation involving an increase in the production of CD80 and CD86 mRNA in the absence of corresponding protein synthesis. Furthermore, intracellular Tax down-regulates the protein expression of molecules involved in antigen presentation. This implies a difference in the mechanism of Tax activity depending upon its location. Additionally, treatment of JAWS II DCs with extracellular Tax decreases the ability of DCs to present a major histocompatibility complex (MHC) class I-restricted peptide, indicating that Tax likely matures the DCs to the point where presentation of a secondary antigen is restricted. The implication of the experimental results with respect to the generation of a Tax-specific CTL compartment that participates in the genesis of HAM/TSP is discussed.
 ...
PMID:Human T-cell leukemia virus type I Tax induces the expression of dendritic cell markers associated with maturation and activation. 1576 7

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