A HISTONE DEACETYLASE COREPRESSOR COMPLEX REGULATES THE NOTCH SIGNAL-TRANSDUCTION PATHWAY

The Delta-Notch signal transduction pathway has widespread roles in an imal development in which it appears to control cell fate. CBF1/RBP-J kappa, the mammalian homolog of Drosophila Suppressor of Hairless [Su( H)], switches from a transcriptional repressor to an activator upon No tch activation. The mechanism whereby Notch regulates this switch is n ot clear. In this report we show that prior to induction CBF1/RBP-J ka ppa interacts with a corepressor complex containing SMRT (silencing me diator of retinoid and thyroid hormone receptors) and the histone deac etylase HDAC-1. This complex binds via the CBF1 repression domain, and mutants defective in repression fail to interact with the complex. Ac tivation by Notch disrupts the formation of the repressor complex, thu s establishing a molecular basis for the Notch switch, finally, ESR-1, a Xenopus gene activated by Notch and X-Su(H), is induced in animal c aps treated with TSA, an inhibitor of HDAC-1. The functional role for the SMRT/HDAC-1 complex in CBF1/RBP-J kappa regulation reveals a novel genetic switch in which extracellular ligands control the status of c ritical nuclear cofactor complexes.