Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

Yunsun Nam, Piotr Sliz, Warren S. Pear, Jon C. Aster, Stephen C. Blacklow

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Notch receptors control differentiation and contribute to pathologic states such as cancer by interacting directly with a transcription factor called CSL (for CBF-1/Suppressor of Hairless/Lag-1) to induce expression of target genes. A number of Notch-regulated targets, including genes of the hairy/enhancer-of- split family in organisms ranging from Drosophila to humans, are characterized by paired CSL-binding sites in a characteristic head-to-head arrangement. Using a combination of structural and molecular approaches, we establish here that cooperative formation of dimeric Notch transcription complexes on promoters with paired sites is required to activate transcription. Our findings identify a mechanistic step that can account for the exquisite sensitivity of Notch target genes to variation in signal strength and developmental context, enable new strategies for sensitive and reliable identification of Notch target genes, and lay the groundwork for the development of Notch pathway inhibitors that are active on target genes containing paired sites.

Original languageEnglish (US)
Pages (from-to)2103-2108
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number7
DOIs
StatePublished - Feb 13 2007

Keywords

  • Dimerization
  • Gene expression
  • Mastermind
  • Notch signaling
  • Signal transduction

ASJC Scopus subject areas

  • General

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