Regulation of nuclear factor of activated T cells by phosphotyrosyl-specific phosphatase activity: a positive effect on HIV-1 long terminal repeat-driven transcription and a possible implication of SHP-1
| Autor: | Gilles A. Robichaud, Michel J. Tremblay, Marie-Ève Paré, Anne-Marie Lemieux, Jean-François Fortin, Benoit Barbeau |
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| Rok vydání: | 2001 |
| Předmět: |
Adult
Transcription Genetic viruses Recombinant Fusion Proteins Immunology Active Transport Cell Nucleus Receptors Antigen T-Cell Protein tyrosine phosphatase Biology Biochemistry Jurkat cells Tacrolimus Jurkat Cells Cyclosporin a Organometallic Compounds Humans Nuclear protein Enzyme Inhibitors Phytohemagglutinins Promoter Regions Genetic Transcription factor HIV Long Terminal Repeat ZAP-70 Protein-Tyrosine Kinase NFATC Transcription Factors Ionomycin Protein Tyrosine Phosphatase Non-Receptor Type 6 Intracellular Signaling Peptides and Proteins NF-kappa B Nuclear Proteins NFAT Cell Biology Hematology Protein-Tyrosine Kinases Molecular biology Recombinant Proteins DNA-Binding Proteins Protein Transport Gene Expression Regulation Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Cyclosporine HIV-1 Interleukin-2 Tetradecanoylphorbol Acetate Signal transduction Protein Tyrosine Phosphatases Immunosuppressive Agents Interleukin-1 Transcription Factors |
| Zdroj: | Blood. 97(8) |
| ISSN: | 0006-4971 |
| Popis: | Although protein tyrosine phosphatase (PTP) inhibitors used in combination with other stimuli can induce interleukin 2 (IL-2) production in T cells, a direct implication of nuclear factor of activated T cells (NFAT) has not yet been demonstrated. This study reports that exposure of leukemic T cells and human peripheral blood mononuclear cells to bis-peroxovanadium (bpV) PTP inhibitors markedly induce activation and nuclear translocation of NFAT. NFAT activation by bpV was inhibited by the immunosuppressive drugs FK506 and cyclosporin A, as well as by a specific peptide inhibitor of NFAT activation. Mobility shift assays showed specific induction of the NFAT1 member by bpV molecules. The bpV-mediated NFAT activation was observed to be important for the up-regulation of the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) and the IL-2 promoter; NFAT1 was demonstrated to be particularly important in bpV-dependent positive action on HIV-1 LTR transcription. The active participation of p56lck, ZAP-70, p21ras, and calcium in the bpV-mediated signaling cascade leading to NFAT activation was confirmed, using deficient cell lines and dominant-negative mutants. Finally, overexpression of wild-type SHP-1 resulted in a greatly diminished activation of NFAT by bpV, suggesting an involvement of SHP-1 in the regulation of NFAT activation. These data were confirmed by constitutive NFAT translocation observed in Jurkat cells stably expressing a dominant-negative version of SHP-1. The study proposes that PTP activity attenuates constitutive kinase activities that otherwise would lead to constant NFAT activation and that this activation is participating in HIV-1 LTR stimulation by PTP inhibition. |
| Databáze: | OpenAIRE |
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