title: T-cell receptor signaling induces proximal Runx1 transactivation via a calcineurin-NFAT pathway.
abstract: Runx1 transcription factor is a key player in the development and function of T cells. Runx1 transcripts consist of two closely related isoforms (proximal and distal Runx1) whose expressions are regulated by different promoters. Which Runx1 isoform is expressed appears to be tightly regulated. The regulatory mechanism for differential transcription is, however, not fully understood. In this study, we investigated the regulation of the proximal Runx1 promoter in T cells. We showed that proximal Runx1 was expressed at a low level in naïve T cells from C57BL/6 mice, but its expression was remarkably induced upon T-cell activation. In the promoter of proximal Runx1, a highly conserved region was identified which spans from -412 to the transcription start site and harbors a NFAT binding site. In a luciferase reporter assay, this region was found to be responsive to T-cell activation through Lck and calcineurin pathways. Mutagenesis studies and chromatin immunoprecipitation assay indicated that the NFAT site was essential for NFAT binding and transactivation of the proximal Runx1 promoter. Furthermore, TCR signaling-induced expression of proximal Runx1 was blocked by treatment of cells with cyclosporin A. Together, these results demonstrate that the calcineurin-NFAT pathway regulates proximal Runx1 transcription upon TCR stimulation.
authors: Faculty of Medicine, Department of Medical Microbiology, University of Malaya, Kuala Lumpur, Malaysia; Department of Molecular Immunology, Institute for Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors: Won Fen
authors: WF
authors: Wong
authors: Chung Yeng
authors: CY
authors: Looi
authors: Shunsuke
authors: S
authors: Kon
authors: Elaheh
authors: E
authors: Movahed
authors: Tomo
authors: T
authors: Funaki
authors: Li Yen
authors: LY
authors: Chang
authors: Masanobu
authors: M
authors: Satake
authors: Kazuyoshi
authors: K
authors: Kohu
mesh_terms: D000818:Animals; D001665:Binding Sites; D019703:Calcineurin / Q000378:metabolism*; D017124:Conserved Sequence; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D016572:Cyclosporine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D009154:Mutation; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D016572:Cyclosporine; D019703:Calcineurin
keywords: Cellular activation; Naive cells; T cells; TCR; Transcription factors