ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors.

Abstract

t(8;21) is one of the most frequent translocations associated with acute myeloid leukemia. It produces a chimeric protein, acute myeloid leukemia-1 (AML-1)-eight-twenty-one (ETO), that contains the amino-terminal DNA binding domain of the AML-1 transcriptional regulator fused to nearly all of ETO. Here we demonstrate that ETO interacts with the nuclear receptor corepressor N-CoR, the mSin3 corepressors, and histone deacetylases. Endogenous ETO also cosediments on sucrose gradients with mSin3A, N-CoR, and histone deacetylases, suggesting that it is a component of one or more corepressor complexes. Deletion mutagenesis indicates that ETO interacts with mSin3A independently of its association with N-CoR. Single amino acid mutations that impair the ability of ETO to interact with the central portion of N-CoR affect the ability of the t(8;21) fusion protein to repress transcription. Finally, AML-1/ETO associates with histone deacetylase activity and a histone deacetylase inhibitor impairs the ability of the fusion protein to repress transcription. Thus, t(8;21) fuses a component of a corepressor complex to AML-1 to repress transcription.

• Authors: B Lutterbach, J J Westendorf, B Linggi, A Patten, M Moniwa, J R Davie, K D Huynh, V J Bardwell, R M Lavinsky, M G Rosenfeld, C Glass, E Seto, S W Hiebert
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 18 Issue 12 Pg. 7176-84 (Dec 1998) ISSN: 0270-7306 [Print] United States
• PMID: 9819404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Core Binding Factor Alpha 2 Subunit
• DNA-Binding Proteins
• NCOR1 protein, human
• Nuclear Proteins
• Nuclear Receptor Co-Repressor 1
• Proto-Oncogene Proteins
• RUNX1 Translocation Partner 1 Protein
• RUNX1 protein, human
• RUNX1T1 protein, human
• Recombinant Fusion Proteins
• Repressor Proteins
• SIN3 protein, S cerevisiae
• Saccharomyces cerevisiae Proteins
• Transcription Factors
• Histone Deacetylases

Topics

• Cell Line
• Chromosomes, Human, Pair 21 (genetics)
• Chromosomes, Human, Pair 8 (genetics)
• Core Binding Factor Alpha 2 Subunit
• DNA-Binding Proteins (genetics)
• Histone Deacetylases (genetics)
• Humans
• Leukemia, Myeloid (genetics)
• Nuclear Proteins (genetics)
• Nuclear Receptor Co-Repressor 1
• Precipitin Tests
• Proto-Oncogene Proteins
• RUNX1 Translocation Partner 1 Protein
• Recombinant Fusion Proteins (genetics)
• Repressor Proteins (genetics)
• Saccharomyces cerevisiae Proteins
• Transcription Factors (genetics)
• Translocation, Genetic (genetics)