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)

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.
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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

HTLV-I is a complex retrovirus that encodes a transcriptional activator, Tax, which regulates expression of the viral promoter. Tax has been shown to be both necessary and sufficient to effect immortalization and transformation of cells in culture and tumorigenesis in animal models. Tax exerts its influence through protein-protein interactions with a variety of molecular targets, including transcription factors and cofactors, histone modifying enzymes and post-translational modifying enzymes. Through these interactions, Tax disrupts cellular regulatory cascades and checkpoints designed to control a variety of systems. The result is untimely activation or repression of gene expression, inappropriate protein modifications, incorrect cell cycling, loss of adequate DNA repair capacity, and potential release of the cell from tumor suppression. Whereas for the virus these functions of Tax provide a means for successful completion of its life cycle, for the cell, they result at best in anarchy, and at worst in death of both the cell and the organism of which that cell is a part.
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PMID:The HTLV-I Tax oncoprotein: hyper-tasking at the molecular level. 1556 4

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.
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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.
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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


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