The role of Ras in T lymphocyte activation.
Ras plays an important role in T cell signal transduction through multiple pathways. Here, we demonstrate that, upon stimulation, increasing Ras activity partially substitutes for calcium-mediated signals leading to IL-2 induction. The increase of Ras activity renders Jurkat cells the resistant to cyclosporin A (CsA) through increasing calcineurin activity. Coincidentally, the inducible binding of NIL-2 to a negative-regulatory element in the IL-2 promoter becomes less sensitive to CsA in the cells with increasing Ras activity. The dose of CsA required for inhibition of IL-2 induction in the cells with increased Ras activity remains similar to the concentration of CsA needed for the suppression of NFAT activation in control cells. The results suggest that Ras regulates calcium/calcineurin signalling during T cell activation and the existence of new immune-related target(s) for CsA action at the posttranscriptional level.
Ma
Peihong
P
Cancer Research Center, R908, Boston University School of Medicine, 80 E. Concord Street, Boston, MA 02118, USA.
Magut
Maureen
M
Faller
Douglas V
DV
Chen
Chang-Yan
CY
D019703:Calcineurin / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005809:Genes, Regulator / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*; D018631:ras Proteins / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin; D018631:ras Proteins