Abstract
Fusion of the promyelocytic leukemia (PML) protein to the retinoic acid receptor-alpha (RARalpha) generates the transforming protein of acute promyelocytic leukemias. PML appears to be involved in multiple functions, including apoptosis and transcriptional activation by RAR, whereas PML-RARalpha blocks these functions of PML. However, the mechanisms of leukemogenesis by PML-RARalpha remain elusive. Here we show that PML interacts with multiple corepressors (c-Ski, N-CoR, and mSin3A) and histone deacetylase 1, and that this interaction is required for transcriptional repression mediated by the tumor suppressor Mad. PML-RARalpha has the two corepressor-interacting sites and inhibits Mad-mediated repression, suggesting that aberrant binding of PML-RARalpha to the corepressor complexes may lead to abrogation of the corepressor function. These mechanisms may contribute to events leading to leukemogenesis.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Leukemic
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Histone Deacetylase 1
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Humans
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Lac Operon
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Leukemia, Promyelocytic, Acute
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Luciferases
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Mammals
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Receptor Co-Repressor 1
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Promyelocytic Leukemia Protein
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Receptors, Retinoic Acid / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Retinoic Acid Receptor alpha
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Sin3 Histone Deacetylase and Corepressor Complex
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Transcription Factors / genetics*
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Transcription Factors / metabolism*
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Transcriptional Activation / physiology*
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Tumor Cells, Cultured
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Tumor Suppressor Proteins
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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MXD1 protein, human
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NCOR1 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Promyelocytic Leukemia Protein
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Proto-Oncogene Proteins
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RARA protein, human
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Receptors, Retinoic Acid
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Repressor Proteins
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Retinoic Acid Receptor alpha
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SIN3A transcription factor
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Transcription Factors
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Tumor Suppressor Proteins
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SKI protein, human
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PML protein, human
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Luciferases
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HDAC1 protein, human
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Histone Deacetylase 1
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Histone Deacetylases
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Sin3 Histone Deacetylase and Corepressor Complex