Abstract
AML1/Evi-1 is a chimeric protein that is derived from t(3;21), found in blastic transformation of chronic myelogenous leukemia. It is composed of the N-terminal AML1 portion with the DNA-binding Runt domain and the C-terminal Evi-1 portion. It has been shown to dominantly repress AML1-induced transactivation. The mechanism for it has been mainly attributed to competition with AML1 for the DNA-binding and for the interaction with PEBP2beta (CBFbeta), a partner protein which heterodimerizes with AML1. It was recently found that Evi-1 interacts with C-terminal binding protein (CtBP) to repress TGFbeta-induced transactivation. Here, we demonstrate that AML1/Evi-1 interacts with CtBP in SKH1 cells, a leukemic cell line which endogenously overexpresses AML1/Evi-1 and that AML1/Evi-1 requires the interaction with CtBP to repress AML1-induced transactivation. The association with CtBP is also required when AML1/Evi-1 blocks myeloid differentiation of 32Dcl3 cells induced by granulocyte colony-stimulating factor. Taken together, it is suggested that one of the mechanisms for AML1/Evi-1-associated leukemogenesis should be an aberrant recruitment of a corepressor complex by the chimeric protein.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohol Oxidoreductases
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Animals
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Artificial Gene Fusion*
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Binding Sites
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Blotting, Northern
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Blotting, Western
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Cell Differentiation
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Chromosomes, Human, Pair 21 / genetics*
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Chromosomes, Human, Pair 3 / genetics*
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Core Binding Factor Alpha 2 Subunit
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Cricetinae
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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DNA-Binding Proteins / pharmacology
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Gene Expression Regulation, Neoplastic
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Granulocyte Colony-Stimulating Factor / pharmacology
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Granulocytes / cytology
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Granulocytes / metabolism
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Histone Deacetylases / metabolism
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Humans
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Leukemia, Myeloid / metabolism*
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MDS1 and EVI1 Complex Locus Protein
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Phosphoproteins / metabolism*
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Precipitin Tests
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Proto-Oncogene Proteins*
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Proto-Oncogenes*
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RNA / metabolism
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Sequence Deletion
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription Factors / pharmacology
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Transcription, Genetic
Substances
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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MDS1 and EVI1 Complex Locus Protein
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MECOM protein, human
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Phosphoproteins
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Proto-Oncogene Proteins
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RUNX1 protein, human
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Transcription Factors
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Granulocyte Colony-Stimulating Factor
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RNA
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Alcohol Oxidoreductases
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C-terminal binding protein
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Histone Deacetylases