Assembly of a notch transcriptional activation complex requires multimerization

Rodrigo Vasquez-Del Carpio, Fred M. Kaplan, Kelly L. Weaver, Jeffrey D. VanWye, Marie Clotilde Alves-Guerra, David J. Robbins, Anthony J. Capobianco

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Notch transmembrane receptors direct essential cellular processes, such as proliferation and differentiation, through direct cell-to-cell interactions. Inappropriate release of the intracellular domain of Notch (NICD) from the plasma membrane results in the accumulation of deregulated nuclear NICD that has been linked to human cancers, notably T-cell acute lymphoblastic leukemia (T-ALL). Nuclear NICD forms a transcriptional activation complex by interacting with the coactivator protein Mastermind-like 1 and the DNA binding protein CSL (for CBF-1/Suppressor of Hairless/Lag-1) to regulate target gene expression. Although it is well understood that NICD forms a transcriptional activation complex, little is known about how the complex is assembled. In this study, we demonstrate that NICD multimerizes and that these multimers function as precursors for the stepwise assembly of the Notch activation complex. Importantly, we demonstrate that the assembly is mediated by NICD multimers interacting with Skip and Mastermind. These interactions form a preactivation complex that is then resolved by CSL to form the Notch transcriptional activation complex on DNA.

Original languageEnglish (US)
Pages (from-to)1396-1408
Number of pages13
JournalMolecular and cellular biology
Volume31
Issue number7
DOIs
StatePublished - Apr 1 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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