T cell leukemia-associated human Notch/translocation-associated Notch homologue 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 cloned from the translocation breakpoint of a human T cell leukemia carrying a 9:7(q34.3) translocation, encodes a protein belonging to the Notch/Lin-12/Glp-1 receptor family. These receptors mediate the specification of numerous cell fates during development in invertebrates and vertebrates. The intracellular portion of Notch/TAN-1 contains six ankyrin repeats that are similar to those found in cytoplasmic I kappa B proteins. I kappa B proteins are specific inhibitors of nuclear factor (NF)-kappa B/Rel transcription factors. Here we show that TAN-1 has functional properties of an I kappa B-like regulator with specificity for the NF-kappa B p50 subunit. A recombinant polypeptide corresponding to the cytoplasmic portion of TAN-1 (TAN-1C) specifically inhibited the DNA binding of p50-containing NF-kappa B complexes. When overexpressed in an appropriate cell line, TAN-1C prevented kappa B-dependent transactivation in transient reporter gene assays in a fashion similar to the structurally related protein, Bcl-3. TAN-1C could activate kappa B-dependent gene expression by attenuating the inhibitory effect of an excess of p50 homodimers. Immunoprecipitation experiments showed that the TAN-1 from a T cell line is associated with NF-kappa B containing p50 and p65 subunits. These observations indicate that TAN-1C may directly engage NF-kappa B transcription factors and modulate nuclear gene expression.
Guan
E
E
Laboratory of Cell Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Wang
J
J
Laborda
J
J
Norcross
M
M
Baeuerle
P A
PA
Hoffman
T
T
D000818:Animals; D002460:Cell Line; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D002899:Chromosomes, Human, Pair 9; D006801:Humans; D007448:Invertebrates; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D051841:Transcription Factor RelB; D014157:Transcription Factors; D015533:Transcriptional Activation; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D014714:Vertebrates
D008565:Membrane Proteins; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051841:Transcription Factor RelB