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.
Pubmed ID: 11533236 RIS Download
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