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Human Notch-1 inhibits NF-kappa B activity in the nucleus through a direct interaction involving a novel domain.

Notch participates in diverse cell fate decisions throughout embryonic development and postnatal life. Members of the NF-kappaB/Rel family of transcription factors are involved in the regulation of a variety of genes important for immune function. The biological activity of the NF-kappaB transcription factors is controlled by IkappaB proteins. Our previous work demonstrated that an intracellular, constitutively active form of human Notch-1/translocation-associated Notch homologue-1 (Notch(IC)) functions as an IkappaB molecule with specificity for the NF-kappaB p50 subunit and physically interacts with NF-kappaB in T cells. In the current study, we investigated the roles of different domains of Notch(IC) in the regulation of NF-kappaB-directed gene expression and NF-kappaB DNA binding activity. We found that Notch(IC) localizes to the nucleus and that a region in the N-terminal portion of Notch(IC), not the six ankyrin repeats, is responsible for the inhibitory effects of Notch on NF-kappaB-directed gene expression and NF-kappaB DNA binding activity. The N-terminal portion of Notch(IC) inhibited p50 DNA binding and interacted specifically with p50 subunit, not p65 of NF-kappaB. The interaction between Notch and NF-kappaB indicates that in addition to its role in the development of the immune system, Notch-1 may also have critical functions in the immune response, inflammation, viral infection, and apoptosis through control of NF-kappaB-mediated gene expression.

Pubmed ID: 11418662


  • Wang J
  • Shelly L
  • Miele L
  • Boykins R
  • Norcross MA
  • Guan E


Journal of immunology (Baltimore, Md. : 1950)

Publication Data

July 1, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: 1R01CA84065-01

Mesh Terms

  • Amino Acid Sequence
  • Binding, Competitive
  • Cell Nucleus
  • DNA-Binding Proteins
  • Gene Expression Regulation
  • Genetic Vectors
  • Humans
  • Intracellular Fluid
  • Jurkat Cells
  • Membrane Proteins
  • Molecular Sequence Data
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Peptide Fragments
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Recombinant Proteins
  • Transcription Factors
  • Tumor Cells, Cultured