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-Jkappa. In the absence of Notch, RBP-Jkappa 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-Jkappa-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Binding Sites
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Cell Cycle Proteins / genetics
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Cell Line
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Cell Line, Tumor
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism*
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression
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HeLa Cells
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Homeodomain Proteins / genetics
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Humans
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism*
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Leukemia, Myeloid / etiology
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Leukemia, Myeloid / genetics
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Leukemia, Myeloid / metabolism
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Mice
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RUNX1 Translocation Partner 1 Protein
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction
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Transcription Factor HES-1
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Transcription Factors / chemistry
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Two-Hybrid System Techniques
Substances
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AML1-ETO fusion protein, human
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BHLHE41 protein, human
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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HEY1 protein, human
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Homeodomain Proteins
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Immunoglobulin J Recombination Signal Sequence-Binding Protein
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MTG8 protein, mouse
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins
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RBPJ protein, human
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RUNX1 Translocation Partner 1 Protein
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RUNX1T1 protein, human
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Receptors, Notch
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Recombinant Fusion Proteins
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Repressor Proteins
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Transcription Factor HES-1
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Transcription Factors
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HES1 protein, human