NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells

FEBS Lett. 2003 Apr 24;541(1-3):163-70. doi: 10.1016/s0014-5793(03)00326-0.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD
  • Base Sequence
  • Binding Sites
  • CD3 Complex / metabolism
  • Cell Line
  • Humans
  • Lymphocyte Activation
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinase Kinases / physiology
  • Mitogen-Activated Protein Kinases / physiology
  • Molecular Sequence Data
  • NF-kappa B / physiology*
  • Promoter Regions, Genetic
  • Receptors, Nerve Growth Factor / biosynthesis
  • Receptors, Nerve Growth Factor / genetics*
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / genetics*
  • Response Elements
  • T-Lymphocytes / immunology*
  • Transcription Factor AP-1 / physiology*
  • Transcriptional Activation*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9


  • Antigens, CD
  • CD3 Complex
  • NF-kappa B
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF9 protein, human
  • Transcription Factor AP-1
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases