NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells.
4-1BB(CD137) is a member of the tumor necrosis factor receptor superfamily and provides a costimulatory signal by interaction with 4-1BB ligand expressed on antigen-presenting cells. The expression of 4-1BB is known to be activation-dependent. Here, we investigated the transcriptional machinery required for T cell receptor (TCR) activation-dependent induction of 4-1BB expression in CD3-CEM cells treated with phorbol myristate acetate and ionomycin. Using 5'-deletion constructs of 4-1BB promoter in luciferase reporter assays, we demonstrated that the transcriptional elements mediating 4-1BB upregulation were located in the region between approximately 0.9 and approximately 1.1 kb from the translational start site. Characterization of these sites by electrophoretic mobility shift assay and site-directed mutagenesis revealed that nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1) are involved. MEK and c-Jun N-terminal kinase-1 activity was required for activation-dependent 4-1BB upregulation. Thus, NF-kappaB and AP-1 are involved in the TCR stimulation-dependent transcriptional regulation of the 4-1BB promoter.
Kim
Jae-Ouk
JO
Laboratory of Immunology and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, South Korea.
Kim
Ho Won
HW
Baek
Kyoung-Min
KM
Kang
Chang-Yuil
CY
D015703:Antigens, CD; D001483:Base Sequence; D001665:Binding Sites; D017252:CD3 Complex / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008213:Lymphocyte Activation; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics*; D020218:Response Elements; D013601:T-Lymphocytes / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D015533:Transcriptional Activation; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D017252:CD3 Complex; D016328:NF-kappa B; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; D018808:Transcription Factor AP-1; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases