A histone deacetylase corepressor complex regulates the Notch signal transduction pathway

Hung Ying Kao, Peter Ordentlich, Naoko Koyano-Nakagawa, Zhenyu Tang, Michael Downes, Chris R. Kintner, Ronald M. Evans, Tom Kadesch

Research output: Contribution to journalArticlepeer-review

491 Scopus citations

Abstract

The Delta-Notch signal transduction pathway has widespread roles in animal development in which it appears to control cell fate. CBF1/RBP-Jκ, the mammalian homolog of Drosophila Suppressor of Hairless [Su(H)], switches from a transcriptional repressor to an activator upon Notch activation. The mechanism whereby Notch regulates this switch is not clear. In this report we show that prior to induction CBF1/RBP-Jκ interacts with a corepressor complex containing SMRT (silencing mediator of retinoid and thyroid hormone receptors) and the histone deacetylase HDAC-1. This complex binds via the CBF1 repression domain, and mutants defective in repression fail to interact with the complex. Activation by Notch disrupts the formation of the repressor complex, thus 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 caps treated with TSA, an inhibitor of HDAC-1. The functional role for the SMRT/HDAC-1 complex in CBF1/RBP-Jκ regulation reveals a novel genetic switch in which extracellular ligands control the status of critical nuclear cofactor complexes.

Original languageEnglish (US)
Pages (from-to)2269-2277
Number of pages9
JournalGenes and Development
Volume12
Issue number15
DOIs
StatePublished - Aug 1 1998
Externally publishedYes

Bibliographical note

Funding Information:
The author wishes to thank Lucien Caro, Don Gerson, Anja Holtz, Raju Pareek, and all our other colleagues for fruitful discussions and critical reading and editing of this chapter. The author also wishes to thank Hiroshi Nikaido for sharing his work before publication and to Harald von Boehmer, Gerhard Hoffmann, Fritz Melchers, Christoph Wilson, Nicolas Burdin, Alexander Aiuti, Gennardo De Libero, Lucia Mori, Patrick Matthias, Ton Rolink, Kris Bowles, and Roger Pedersen for giving permission to use figures and tables and for conducting kind discussions and for providing inside information on their work. This work is supported by funds from third-party agencies: German DFG, the European Community, W-P, CMU.

Keywords

  • CBF1/RBP-Jκ
  • Corepressor complex
  • Notch
  • SMRT
  • Transcriptional repressor

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