T-CELL LEUKEMIA-ASSOCIATED HUMAN NOTCH TRANSLOCATION-ASSOCIATED NOTCHHOMOLOG HAS I-KAPPA-B-LIKE ACTIVITY AND PHYSICALLY INTERACTS WITH NUCLEAR FACTOR-KAPPA-B PROTEINS IN T-CELLS

Translocation-associated Notch homologue (TAN-1), a gene originally cl oned from the translocation breakpoint of a human T cell leukemia carr ying a 9:7(q34.3) translocation, encodes a protein belonging to the No tch/Lin-12/Glp-1 receptor family. These receptors mediate the specific ation of numerous cell fates during development in invertebrates and v ertebrates. The intracellular portion of Notch/TAN-1 contains six anky rin repeats that are similar to those found in cytoplasmic I kappa B p roteins. I kappa B proteins are specific inhibitors of nuclear factor (NF)-kappa B/Rel transcription factors. Here we show that TAN-1 has fu nctional properties of an I kappa B-like regulator with specificity fo r the NF-kappa B p50 subunit. A recombinant polypeptide corresponding to the cytoplasmic portion of TAN-1 (TAN-1(C)) specifically inhibited the DNA binding of p50-containing NF-kappa B complexes. When overexpre ssed in an appropriate cell Line, TAN-le prevented kappa B-dependent t ransactivation in transient reporter gene assays in a fashion similar to the structurally related protein, Bcl-3. TAN-1(C) could activate ka ppa B-dependent gene expression by attenuating the inhibitory effect o f an excess of p50 homodimers. Immunoprecipitation experiments showed that the TAN-1 from a T cell line is associated with NF-kappa B contai ning p50 and p65 subunits. These observations indicate that TAN-1(C) m ay directly engage NF-kappa B transcription factors and modulate nucle ar gene expression.