Somatic mutagenesis studies of NF-kappa B signaling in human T cells: evidence for an essential role of IKK gamma in NF-kappa B activation by T-cell costimulatory signals and HTLV-I Tax protein

Oncogene. 2000 Mar 9;19(11):1448-56. doi: 10.1038/sj.onc.1203445.

Abstract

NF-kappa B plays a pivotal role in normal T-cell activation and may also mediate human T-cell leukemia virus (HTLV)-induced T-cell transformation. Activation of NF-kappa B by both T-cell costimulatory signals and the HTLV Tax protein involves stimulation of I kappa B kinase (IKK). As a genetic approach to dissect the intermediate steps involved in NF-kappa B activation in human T cells, we performed somatic cell mutagenesis to isolate signaling-defective mutant Jurkat T-cell lines. One of the mutant cell lines was shown to have a specific blockade in the IKK signaling pathway but remained competent in the c-Jun N-terminal kinase and MAP kinase pathways. Interestingly, this mutant cell line lacks expression of IKK gamma, a non-catalytic component of the IKK complex. Expression of exogenous IKK gamma in the mutant cells restored NF-kappa B activation by both the T-cell costimulation agents and Tax. These findings provide genetic evidence for the requirement of IKK gamma in NF-kappa B signaling triggered by both T-cell costimulatory signals and HTLV-I Tax protein.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • CD28 Antigens / immunology
  • CD3 Complex / immunology
  • Cell Line
  • Cell Separation
  • Gene Products, tax / immunology*
  • Human T-lymphotropic virus 1 / immunology*
  • Humans
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • Jurkat Cells
  • Lymphocyte Activation* / drug effects
  • Lymphocyte Activation* / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogens / pharmacology
  • Mutagenesis*
  • NF-kappa B / deficiency
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Signal Transduction / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology*
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Antibodies, Monoclonal
  • CD28 Antigens
  • CD3 Complex
  • Gene Products, tax
  • Mitogens
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate