The role of NFATp in cyclosporin A-sensitive tumor necrosis factor-alpha gene transcription.
The tumor necrosis factor-alpha (TNF alpha) gene is an immediate early gene in activated T cells, in that it is rapidly induced without a requirement for protein synthesis. Maximal induction of TNF alpha mRNA can be induced by treatment of T cells with calcium ionophores alone, via a calcineurin-dependent process that is blocked by cyclosporin A. We have previously identified a promoter element, kappa 3, that is required for calcium-stimulated, cyclosporin A-sensitive induction of the TNF alpha gene in activated T cells. Here, we demonstrate that the kappa 3 binding factor contains NFATp, a cyclosporin-sensitive DNA-binding protein required for interleukin-2 gene transcription. NFATp binds to two sites within the kappa 3 element, and occupancy of both sites is required for TNF alpha gene induction. Thus, although the kappa 3 element has little sequence similarity to other NFATp-binding sites, it appears to function as a cyclosporin-sensitive promoter element in T cells by virtue of its ability to bind NFATp. The involvement of NFATp in transcriptional activation of both the interleukin-2 and TNF alpha genes suggests that this factor plays an important role in the coordinate induction of multiple cytokine genes, starting at the earliest stages of T cell activation.
McCaffrey
P G
PG
Division of Tumor Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Goldfeld
A E
AE
Rao
A
A
D001483:Base Sequence; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D016572:Cyclosporine / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013601:T-Lymphocytes; D014157:Transcription Factors / Q000302:isolation & purification / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine