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Molecular and Cellular Biology, November 2001, p. 7761-7774, Vol. 21, No. 22
Departments of Internal
Medicine1 and
Pediatrics,3 University of Ulm, D-89081
Ulm, and Institute for Medical Microbiology and Hygiene,
University of Regensburg, D-93053 Regensburg,2
Germany
Received 16 March 2001/Returned for modification 29 April
2001/Accepted 2 August 2001
Notch-1 belongs to a family of transmembrane receptor proteins that
direct the decisions as to various cell fates. After ligand binding, a
proteolytic cleavage step occurs and the intracellular part of Notch-1,
Notch-1-IC, translocates into the nucleus, where it targets the DNA
binding protein RBP-J
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.22.7761-7774.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
p300 Acts as a Transcriptional Coactivator for Mammalian
Notch-1
/CBF1. RBP-J
mediates repression through
recruitment of a histone deacetylase-containing complex. The
Notch-1-IC/RBP-J
complex overcomes repression and activates the
transcription of Notch target genes. We have identified a novel domain
in Notch-1-IC, the EP domain, which is indispensable for full
transcriptional activation. This transactivation domain is localized
adjacent to the ankyrin repeats of Notch-1-IC. In cotransfection
experiments, Notch-1-IC-mediated transcriptional activation was
inhibited by E1A12S and p53, two proteins, which interfere with the
function of the common coactivator p300. Protein-protein interaction
assays demonstrated the association of Notch-1-IC and the CH3 region of
p300. In addition, the interaction of mammalian Notch-1-IC with p300
was destabilized after deletion of the EP domain of Notch-1-IC. Based
on physical interaction with Notch-1-IC and coactivator functions of
p300, we propose a model for Notch-1-mediated gene regulation via p300.
*
Corresponding author. Mailing address: Department
of Internal Medicine I, Robert-Koch-Strasse 8, D-89081 Ulm,
Germany. Phone: 49-731-50-24305. Fax: 49-731-50-24302. E-mail:
roland.schmid{at}medizin.uni-ulm.de.
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