Menin critically links MLL proteins with LEDGF on cancer-associated target genes.
Menin displays the unique ability to either promote oncogenic function in the hematopoietic lineage or suppress tumorigenesis in the endocrine lineage; however, its molecular mechanism of action has not been defined. We demonstrate here that these discordant functions are unified by menin's ability to serve as a molecular adaptor that ... physically links the MLL (mixed-lineage leukemia) histone methyltransferase with LEDGF (lens epithelium-derived growth factor), a chromatin-associated protein previously implicated in leukemia, autoimmunity, and HIV-1 pathogenesis. LEDGF is required for both MLL-dependent transcription and leukemic transformation. Conversely, a subset of menin mutations in multiple endocrine neoplasia type 1 patients abrogate interaction with LEDGF while preserving MLL interaction but nevertheless compromise MLL/menin-dependent functions. Thus, LEDGF critically associates with MLL and menin at the nexus of transcriptional pathways that are recurrently targeted in diverse diseases.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Cell Transformation, Neoplastic, Chromatin, Chromatin Assembly and Disassembly, Gene Expression Regulation, Leukemic, Hela Cells, Histone-Lysine N-Methyltransferase, Homeodomain Proteins, Humans, Leukemia, Mice, Mice, Inbred C57BL, Multiple Endocrine Neoplasia Type 1, Mutation, Myeloid Progenitor Cells, Myeloid-Lymphoid Leukemia Protein, Protein Binding, Protein Methyltransferases, Protein Structure, Tertiary, Proto-Oncogene Proteins, RNA Interference, Time Factors, Transcription Factors, Transcription, Genetic, Transduction, Genetic, Tumor Suppressor Proteins, U937 Cells
Adaptor Proteins, Signal Transducing, Animals, Cell Transformation, Neoplastic, Chromatin, Chromatin Assembly and Disassembly, Gene Expression Regulation, Leukemic, Hela Cells, Histone-Lysine N-Methyltransferase, Homeodomain Proteins, Humans, Leukemia, Mice, Mice, Inbred C57BL, Multiple Endocrine Neoplasia Type 1, Mutation, Myeloid Progenitor Cells, Myeloid-Lymphoid Leukemia Protein, Protein Binding, Protein Methyltransferases, Protein Structure, Tertiary, Proto-Oncogene Proteins, RNA Interference, Time Factors, Transcription Factors, Transcription, Genetic, Transduction, Genetic, Tumor Suppressor Proteins, U937 Cells
Cancer Cell
Date: Jul. 08, 2008
PubMed ID: 18598942
View in: Pubmed Google Scholar
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