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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.

Pubmed ID: 18598942

Authors

  • Yokoyama A
  • Cleary ML

Journal

Cancer cell

Publication Data

July 8, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA116606
  • Agency: NCI NIH HHS, Id: CA55029
  • Agency: NCI NIH HHS, Id: R01 CA055029
  • Agency: NCI NIH HHS, Id: R01 CA055029-18
  • Agency: NCI NIH HHS, Id: R01 CA116606
  • Agency: NCI NIH HHS, Id: R01 CA116606-04

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