title: Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2/Jun and NFATp.
abstract: The human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest genes expressed upon the activation of a T or B cell through its antigen receptor. Previous experiments have demonstrated that in stimulated T cells, a TNF-alpha promoter element, kappa 3, which binds NFATp, is required for the cyclosporin A-sensitive transcriptional activation of the gene. Here, we demonstrate that a cyclic AMP response element (CRE), which lies immediately upstream of the kappa 3 site, is also required for induction of TNF-alpha gene transcription in T cells stimulated by calcium ionophore or T-cell receptor ligands. The CRE binds ATF-2 and Jun proteins in association with NFATp bound to kappa 3. These proteins bind noncooperatively in vitro; however, the transcriptional activity of the CRE/kappa 3 composite site is dramatically higher than the activity of the kappa 3 site alone, indicating that the two sites cooperate in vivo. This study is the first demonstration of a role for ATF-2 in TNF-alpha gene transcription and of a functional interaction between ATF-2/Jun and NFATp. This novel pairing of NFATp with ATF-2/Jun may account for the specific and immediate pattern of TNF-alpha gene transcription in stimulated T cells.
authors.affiliation: Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: E Y
authors.initials: EY
authors.lastname: Tsai
authors.forename: J
authors.initials: J
authors.lastname: Jain
authors.forename: P A
authors.initials: PA
authors.lastname: Pesavento
authors.forename: A
authors.initials: A
authors.lastname: Rao
authors.forename: A E
authors.initials: AE
authors.lastname: Goldfeld
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051790:G-Box Binding Factors; D005786:Gene Expression Regulation; D006801:Humans; D007476:Ionophores / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D051790:G-Box Binding Factors; D007476:Ionophores; D008024:Ligands; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium