Abstract
The translocation t(12;22)(p13;q11) creates an MN1-TEL fusion gene leading to acute myeloid leukemia. MN1 is a transcription coactivator of the retinoic acid and vitamin D receptors, and TEL (ETV6) is a member of the E26-transformation-specific family of transcription factors. In MN1-TEL, the transactivating domains of MN1 are combined with the DNA-binding domain of TEL. We show that MN1-TEL inhibits retinoic acid receptor (RAR)-mediated transcription, counteracts coactivators such as p160 and p300, and acts as a dominant-negative mutant of MN1. Compared to MN1, the same transactivation domains in MN1-TEL are poorly stimulated by p160, p300 or histone deacetylase inhibitors, indicating that the block of RAR-mediated transcription by MN1-TEL is caused by dysfunctional transactivation domains rather than by recruitment of corepressors. The mechanism leading to myeloid leukemia in t(12;22) thus differs from the translocations that involve RAR itself.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / pathology*
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Chromosomes, Human, Pair 12 / genetics
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Chromosomes, Human, Pair 22 / genetics
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DNA-Binding Proteins
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E1A-Associated p300 Protein / physiology
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Enzyme Inhibitors
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Genes, Dominant
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Histone Deacetylase Inhibitors
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology
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Mutation
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Nuclear Proteins / physiology
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Nucleocytoplasmic Transport Proteins / physiology
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Oncogene Proteins, Fusion / physiology*
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RNA-Binding Proteins
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Receptors, Retinoic Acid / genetics*
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Retinoid X Receptors / genetics*
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / physiology*
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Transcription, Genetic*
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Transcriptional Activation
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Transfection
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Translocation, Genetic
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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MN1-TEL fusion protein, human
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MYBBP1A protein, human
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Nuclear Proteins
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Nucleocytoplasmic Transport Proteins
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Oncogene Proteins, Fusion
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RNA-Binding Proteins
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Transcription Factors
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E1A-Associated p300 Protein
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EP300 protein, human