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Human Notch-1 Inhibits NF-B Activity in the Nucleus Through a Direct Interaction Involving a Novel Domain¹

Laboratory of Gene Regulation, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892

Notch participates in diverse cell fate decisions throughout embryonic development and postnatal life. Members of the NF-B/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-B transcription factors is controlled by IB 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 IB molecule with specificity for the NF-B p50 subunit and physically interacts with NF-B in T cells. In the current study, we investigated the roles of different domains of Notch^IC in the regulation of NF-B-directed gene expression and NF-B 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-B-directed gene expression and NF-B DNA binding activity. The N-terminal portion of Notch^IC inhibited p50 DNA binding and interacted specifically with p50 subunit, not p65 of NF-B. The interaction between Notch and NF-B 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-B-mediated gene expression.

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