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PMID: 18598942 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Menin critically links MLL proteins with LEDGF on cancer-associated target genes.

Cancer cell ·Vol. 14 ·No. 1 ·2008-07-08 ·Pages 36-46

Yokoyama A, Cleary ML

Abstract

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/genetics,metabolism Animals Cell Transformation, Neoplastic/genetics,metabolism,pathology Chromatin/metabolism Chromatin Assembly and Disassembly Gene Expression Regulation, Leukemic HeLa Cells Histone Methyltransferases Histone-Lysine N-Methyltransferase/metabolism Homeodomain Proteins/genetics,metabolism Humans Leukemia/enzymology,genetics,metabolism,pathology Mice Mice, Inbred C57BL Multiple Endocrine Neoplasia Type 1/genetics,metabolism Mutation Myeloid Progenitor Cells/enzymology,metabolism Myeloid-Lymphoid Leukemia Protein/genetics,metabolism Protein Binding Protein Methyltransferases Protein Structure, Tertiary Proto-Oncogene Proteins/genetics,metabolism RNA Interference Time Factors Transcription Factors/genetics,metabolism Transcription, Genetic Transduction, Genetic Tumor Suppressor Proteins/genetics,metabolism U937 Cells
Chemicals
Adaptor Proteins, Signal Transducing Chromatin Homeodomain Proteins KMT2A protein, human MEN1 protein, human PSIP1 protein, human Proto-Oncogene Proteins Transcription Factors Tumor Suppressor Proteins homeobox protein HOXA9 Myeloid-Lymphoid Leukemia Protein Histone Methyltransferases Protein Methyltransferases Histone-Lysine N-Methyltransferase
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Yokoyama Akihiko
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. [email protected]
Cleary Michael L
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2008.05.003
Email
[email protected]
Published
2008-07-08
Pages
36-46
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2692591
Subset
IM
Grants
NCI NIH HHS · CA55029 · United States
NCI NIH HHS · R01 CA055029 · United States
NCI NIH HHS · R01 CA055029-18 · United States
NCI NIH HHS · CA116606 · United States
NCI NIH HHS · R01 CA116606 · United States
NCI NIH HHS · R01 CA116606-04 · United States
Corrections
CommentIn
PMID: 18598937
External Links
PubMed source DOI: 10.1016/j.ccr.2008.05.003 PMC Full Text View journal details
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