SRC-related proto-oncogenes and transcription factors in primary human T cells: modulation by cyclosporin A and FK506.
Activation of T lymphocytes induces transcription of genes encoding for lymphokines. Interleukin-2 (IL-2) gene expression is controlled transcriptionally by the cooperative activity of specific trans-activating factors that bind to the IL-2 enhancer. Cyclosporin A (CsA) and FK506 inhibit the production of IL-2 in T lymphocytes at the level of gene transcription. A member of the src gene family, the lymphocyte-specific protein tyrosine kinase, p56lck, has been implicated in IL-2 production. CsA was found not to inhibit lck gene expression, nor the activity of the lck gene product. However, CsA and FK506 inhibit the appearance of DNA binding activity of factors that bind to the NF-AT and AP-1 sites in the IL-2 enhancer. Since the induction of NF-AT and AP-1 is induced by the same stimuli that stimulate IL-2 production, these results indicate that the immunosuppressant action of CsA and FK506 is exerted at the level of these trans-activating factors.
Granelli-Piperno
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Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10021.
D015152:Blotting, Northern; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D016391:Genes, src / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000096:biosynthesis; D012313:RNA / Q000032:analysis; D015347:RNA Probes; D013601:T-Lymphocytes / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008070:Lipopolysaccharides; D015347:RNA Probes; D014157:Transcription Factors; D012313:RNA; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D016392:Proto-Oncogene Proteins pp60(c-src); D016559:Tacrolimus