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ETO, but Not Leukemogenic Fusion Protein AML1/ETO, Augments RBP-J/SHARP-Mediated Repression of Notch Target Genes ^,

Daniela Salat,^1, Robert Liefke,^4, Jörg Wiedenmann,^2,3 Tilman Borggrefe,^4* and Franz Oswald^1*

Department of Internal Medicine I,¹ Department of Zoology and Endocrinology, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany,² School of Ocean and Earth Science, National Oceanographic Centre, University of Southampton, SO14 3ZH Southampton, United Kingdom,³ Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology, Stübeweg 51, 79108 Freiburg, Germany⁴

Received 31 October 2007/ Returned for modification 27 December 2007/ Accepted 3 March 2008

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 ETO is found at Notch target gene promoters. In functional assays, corepressor ETO, but not AML1/ETO, augments SHARP-mediated repression in an histone deacetylase-dependent manner. Furthermore, either the knockdown of ETO or the 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.

Published ahead of print on 10 March 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors made equal contributions.