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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.
- Source :
-
Blood [Blood] 2001 Apr 15; Vol. 97 (8), pp. 2390-400. - Publication Year :
- 2001
-
Abstract
- 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 p56(lck), ZAP-70, p21(ras), 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.
- Subjects :
- Active Transport, Cell Nucleus
Adult
Cyclosporine pharmacology
Enzyme Inhibitors pharmacology
Gene Expression Regulation drug effects
Gene Expression Regulation physiology
Humans
Immunosuppressive Agents pharmacology
Interleukin-1 genetics
Interleukin-2 pharmacology
Intracellular Signaling Peptides and Proteins
Ionomycin pharmacology
Jurkat Cells drug effects
Jurkat Cells metabolism
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) deficiency
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) physiology
NF-kappa B physiology
NFATC Transcription Factors
Organometallic Compounds pharmacology
Phytohemagglutinins pharmacology
Promoter Regions, Genetic drug effects
Protein Transport
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases antagonists & inhibitors
Protein-Tyrosine Kinases physiology
Receptors, Antigen, T-Cell physiology
Recombinant Fusion Proteins biosynthesis
Recombinant Proteins pharmacology
Tacrolimus pharmacology
Tetradecanoylphorbol Acetate pharmacology
ZAP-70 Protein-Tyrosine Kinase
DNA-Binding Proteins physiology
HIV Long Terminal Repeat physiology
HIV-1 physiology
Nuclear Proteins
Protein Tyrosine Phosphatases physiology
Transcription Factors physiology
Transcription, Genetic drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 97
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 11290602
- Full Text :
- https://doi.org/10.1182/blood.v97.8.2390