Abstract
MLL is involved in chromosomal rearrangements that generate fusion proteins with deregulated transcriptional activity. The mechanisms of MLL fusion protein-mediated transcriptional activation are poorly understood. Here we show MLL interacts directly with the polymerase associated factor complex (PAFc) through sequences flanking the CxxC domain. PAFc interacts with RNA polymerase II and stimulates posttranslational histone modifications. PAFc augments MLL and MLL-AF9 mediated transcriptional activation of Hoxa9. Conversely, knockdown of PAFc disrupts MLL fusion protein-mediated transcriptional activation and MLL recruitment to target loci. PAFc gene expression is downregulated during hematopoiesis and likely serves to regulate MLL function. Deletions of MLL that abolish interactions with PAFc also eliminate MLL-AF9 mediated immortalization indicating an essential function for this interaction in leukemogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Differentiation / genetics
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Cell Line
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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DNA / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Down-Regulation / genetics
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Gene Expression Regulation
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HL-60 Cells
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HeLa Cells
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Homeodomain Proteins / genetics*
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Humans
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Leukemia / genetics
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Leukemia / metabolism*
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Mice
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Mice, Inbred C57BL
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Models, Biological
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Myeloid Cells / cytology
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Myeloid Cells / metabolism
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Neoplasm Proteins / genetics
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Binding / physiology
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Protein Interaction Domains and Motifs / physiology
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RNA Interference
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Deletion / physiology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic / physiology
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Transcriptional Activation / genetics
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Transfection
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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CDC73 protein, human
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CTR9 protein, human
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Carrier Proteins
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DNA-Binding Proteins
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E2a-Hlf fusion protein, human
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Homeodomain Proteins
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LEO1 protein, human
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MLL-AF9 fusion protein, human
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MLL-ENL oncoprotein, human
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Neoplasm Proteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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PAF1 protein, human
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Phosphoproteins
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RNA polymerase II associated factor 1, mouse
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Recombinant Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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homeobox protein HOXA9
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Myeloid-Lymphoid Leukemia Protein
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DNA