Abstracts (poster) - Wissenschaft Online

Robert Liefke, Daniela Salat, Jörg Wiedenmann, Franz Oswald, Tilman Borggrefe
ETO, but not AML1/ETO, augments RBP-Jk/Sharp-mediated
transcriptional repression of Notch target genes
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 (Notch-IC)
translocates to the nucleus, where it targets the DNA
binding protein RBP-Jκ/CBF1 (reviewed in 1). In the
absence of Notch, RBP-Jκ represses Notch target
genes through recruitment of a corepressor complex.
We and others have identified SHARP, CtIP and CtBP
as a component of this complex (3, 4, 5). Here, we
show that co-repressor ETO, as well as the
leukemogenic fusion protein AML1/ETO, directly
interact with SHARP, that ETO is part of the
endogenous RBP-Jκ-containing co-repressor
complex and that it is found at the Notch target gene
promoters in ChIP experiments. In functional assays
co-repressor ETO, but not leukemogenic fusion
protein AML1/ETO, augments SHARP-mediated
repression. Furthermore, overexpression of
AML1/ETO activates endogenous Notch target genes
whereas knock-down of AML1/ETO leads to
downregulation of Notch target genes. Therefore, we
propose that AML1/ETO can disturb the normal,
repressive function of ETO at Notch target genes.
This activating (derepressing) effect of AML1/ETO
may contribute to its oncogenic potential in myeloid
leukemia.
Literature
1) Bray SJ.. (2006) Nat Rev Mol Cell Biol 7:678-89.
2) Licht JD (2001) Oncogene 20:566079
3) Oswald, F., et al. (2002) Embo J 21:5417-26.
4) Kuroda, K. et al. (2003) Immunity 18:301-12.
5) Oswald, F. et al. (2005) Mol Cell Biol 25:10379-90
contact:
Robert Liefke
Max-Planck Institute of Immunobiology
liefke@immunbio.mpg.de
Stübeweg 51
79108 Freiburg (Germany)