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Mol. Cell. Biol. doi:10.1128/MCB.01966-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

ETO, but not leukemogenic fusion protein AML1/ETO, augments RBP-J/SHARP-mediated repression of Notch target genes

Department of Internal Medicine I, Department of Zoology and Endocrinology, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany; School of Ocean and Earth Science, National Oceanographic Centre, University of Southampton, SO14 3ZH Southampton, UK; School of Ocean and Earth Science, National Oceanographic Centre, SO14 3ZH Southampton, Department of Cellular and Molecular Immunology, Max-Planck-Institute of Immunobiology, Stübeweg 51, 79108 Freiburg, Germany

^* To whom correspondence should be addressed. Email: borggrefe{at}immunbio.mpg.de.

	Abstract

Notch is a transmembrane receptor that determines cell fates and pattern formation in all animal species. After specific ligand binding, the intracellular part of Notch is cleaved off and translocates to the nucleus, where it targets the DNA binding protein RBP-J. In the absence of Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. We and others have previously identified SHARP as one component of this complex. Here, we show that the corepressor ETO, as well as the leukemogenic fusion protein AML1/ETO, directly interacts with SHARP, that ETO is part of the endogenous RBP-J-containing corepressor complex, and that it is found at Notch target gene promoters. In functional assays corepressor ETO, but not AML1/ETO, augments SHARP-mediated repression in an HDAC-dependent manner. Furthermore, either ETO knock-down or overexpression of AML1/ETO activates Notch target genes. Therefore, we propose that AML1/ETO can disturb the normal, repressive function of ETO at Notch target genes. This activating (or derepressing) effect of AML1/ETO may contribute to its oncogenic potential in myeloid leukemia.

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