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Molecular and Cellular Biology, December 2005, p. 10379-10390, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10379-10390.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

RBP-J{kappa}/SHARP Recruits CtIP/CtBP Corepressors To Silence Notch Target Genes

Franz Oswald,1* Michael Winkler,2 Ying Cao,3 Kathy Astrahantseff,3 Soizic Bourteele,1 Walter Knöchel,3 and Tilman Borggrefe4*

Department of Internal Medicine I,1 Department of Virology,2 Department of Biochemistry,3 Department of Immunology, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany4

Received 28 July 2005/ Returned for modification 24 August 2005/ Accepted 19 September 2005

Notch is a transmembrane receptor that determines cell fates and pattern formation in all animal species. After ligand binding, proteolytic cleavage steps occur and the intracellular part of Notch translocates to the nucleus, where it targets the DNA-binding protein RBP-J{kappa}/CBF1. In the absence of Notch, RBP-J{kappa} represses Notch target genes through the recruitment of a corepressor complex. We and others have identified SHARP as a component of this complex. Here, we functionally demonstrate that the SHARP repression domain is necessary and sufficient to repress transcription and that the absence of this domain causes a dominant negative Notch-like phenotype. We identify the CtIP and CtBP corepressors as novel components of the human RBP-J{kappa}/SHARP-corepressor complex and show that CtIP binds directly to the SHARP repression domain. Functionally, CtIP and CtBP augment SHARP-mediated repression. Transcriptional repression of the Notch target gene Hey1 is abolished in CtBP-deficient cells or after the functional knockout of CtBP. Furthermore, the endogenous Hey1 promoter is derepressed in CtBP-deficient cells. We propose that a corepressor complex containing CtIP/CtBP facilitates RBP-J{kappa}/SHARP-mediated repression of Notch target genes.

* Corresponding author. Mailing address for Franz Oswald: Department of Internal Medicine I, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany. Phone: 49-731-500-24369. Fax: 49-731-500-24302. E-mail: franz.oswald{at}uni-ulm.de. Mailing address for Tilman Borggrefe: Department of Cellular and Molecular Immunology, Max-Planck Institute of Immunobiology, Stübeweg 51, 79108 Freiburg, Germany. Phone: 49-761-5108-693. Fax: 49-761-5108-799. E-mail: borggrefe{at}immunbio.mpg.de.

Molecular and Cellular Biology, December 2005, p. 10379-10390, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10379-10390.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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