ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain.
t(8;21) and t(16;21) create two fusion proteins, AML-1-ETO and AML-1-MTG16, respectively, which fuse the AML-1 DNA binding domain to putative transcriptional corepressors, ETO and MTG16. Here, we show that distinct domains of ETO contact the mSin3A and N-CoR corepressors and define two binding sites within ETO for each of these ... corepressors. In addition, of eight histone deacetylases (HDACs) tested, only the class I HDACs HDAC-1, HDAC-2, and HDAC-3 bind ETO. However, these HDACs bind ETO through different domains. We also show that the murine homologue of MTG16, ETO-2, is also a transcriptional corepressor that works through a similar but distinct mechanism. Like ETO, ETO-2 interacts with N-CoR, but ETO-2 fails to bind mSin3A. Furthermore, ETO-2 binds HDAC-1, HDAC-2, and HDAC-3 but also interacts with HDAC-6 and HDAC-8. In addition, we show that expression of AML-1-ETO causes disruption of the cell cycle in the G(1) phase. Disruption of the cell cycle required the ability of AML-1-ETO to repress transcription because a mutant of AML-1-ETO, Delta469, which removes the majority of the corepressor binding sites, had no phenotype. Moreover, treatment of AML-1-ETO-expressing cells with trichostatin A, an HDAC inhibitor, restored cell cycle control. Thus, AML-1-ETO makes distinct contacts with multiple HDACs and an HDAC inhibitor biologically inactivates this fusion protein.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, Cell Line, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Enzyme Inhibitors, Histone Deacetylase Inhibitors, Histone Deacetylases, Hydroxamic Acids, Leukemia, Myelomonocytic, Acute, Mice, Models, Genetic, Molecular Sequence Data, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Oncogene Proteins, Fusion, Protein Structure, Tertiary, Proto-Oncogene Proteins, Repressor Proteins, Sequence Homology, Amino Acid, Transcription Factors, Transcription, Genetic, Translocation, Genetic
Amino Acid Sequence, Animals, Binding Sites, Cell Line, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Enzyme Inhibitors, Histone Deacetylase Inhibitors, Histone Deacetylases, Hydroxamic Acids, Leukemia, Myelomonocytic, Acute, Mice, Models, Genetic, Molecular Sequence Data, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Oncogene Proteins, Fusion, Protein Structure, Tertiary, Proto-Oncogene Proteins, Repressor Proteins, Sequence Homology, Amino Acid, Transcription Factors, Transcription, Genetic, Translocation, Genetic
Mol. Cell. Biol.
Date: Oct. 01, 2001
PubMed ID: 11533236
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