Human notch-1 inhibits NF-kappa B activity in the nucleus through a directinteraction involving a novel domain

Notch participates in diverse cell fate decisions throughout embryonic deve lopment and postnatal life. Members of the NF-kappaB/Rel family of transcri ption factors are involved in the regulation of a variety of genes importan t for immune function. The biological activity of the NF-kappaB transcripti on factors is controlled by I kappaB proteins. Our previous work demonstrat ed that an intracellular, constitutively active form of human Notch-1/trans location-associated Notch homologue-1 (Notch(IC)) functions as an I kappaB molecule with specificity for the NF-kappaB p50 subunit and physically inte racts 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-dire cted gene expression and NF-kappab DNA binding activity. We found that Notc h(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 inhibitor y 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 bin ding and interacted specifically with p50 subunit, not p65 of NF-kappaB. Th e 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 critic al functions in the immune response, inflammation, viral infection, and apo ptosis through control of NF-kappaB-mediated gene expression.