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FLASH GENE
Symbol MEN1 contributors: mct/pgu - updated : 12-05-2013
HGNC name multiple endocrine neoplasia I
HGNC id 7010
DNA
TYPE functioning gene
STRUCTURE 7.78 kb     11 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence
text structure
  • five large adjacent cis-regulatory regions (UR1-UR5) exist upstream of this minimal promoter region, whose activity depend not only on the cellular context but also on the presence of a downstream sequence DR1
  • five small cis-regulatory elements (C1-C5) are localized between -325 and -107
    • MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 - 2785 67.8 615 - 1997 9253601
  • isoform 1
    • 10 splicing 2748 67.8 615 - 1997 9253601
  • variant e1B, differing by its 5'utr
  • isoform 1
    • 10 splicing 2736 67.8 615 - 1997 9253601
  • variant e1C, differing by its 5'utr
  • isoform 1
    • 10 splicing 3172 67.8 615 - 1997 9253601
  • variant e1D, differing by its 5'utr
  • isoform 1
    • 10 splicing 3179 67.8 615 - 1997 9253601
  • variant e1E, differing by its 5'utr
  • isoform 1
    • 10 splicing 2770 67.3 610 - 1997 9253601
  • isoform 2
    • 11 splicing 3051 67.8 615 - 1997 9253601
  • variant e1F1, isoform 1
    		•
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivesalivary gland   highly
    Lymphoid/Immunelymph node   highly
    Reproductivefemale systemuterus  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two nuclear localization signals (NLS)
  • a deep pocket that binds short peptides of MLL or JUND in the same manner, but it can have opposite effects on transcription
    • HOMOLOGY
    interspecies homolog to murine Men1
    Homologene
    FAMILY
    CATEGORY regulatory , transcription factor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • dual role as a tumor suppressor and a oncogenic cofactor
  • transcriptional repressor through interaction with the transcription factor JUND by an histone deacetylase dependent mechanism
  • atypical GTPase stimulated by NME1
  • playing an important role for both early differentiation of osteoblasts and inhibition of their later differentiation, and it might be crucial for intramembranous ossification
  • is required for both initiation and maintenance of transformation by MLL oncogenes
  • key regulator of gene networks that are activated in fibrogenesis associated with hepatocellular carcinoma through the modulation of TGF-beta response
  • involved in cell migration and cell adhesion
  • may be involved in DNA repair
  • augmenting PPARG target gene expression through recruitment of H3K4 methyltransferase activity, thus it is an important factor in PPARG-mediated adipogenesis
  • may control cell proliferation through suppression of Wnt/beta-catenin signaling
  • is a molecular adaptor coordinating the functions of multiple proteins
  • stimulates homology-directed (HD) DNA repair and it accumulates with CHEK1 at the site of the double strand break
  • important novel negative regulator of AKT1 kinase activity
  • plays a key role in controlling histone 3 lysine 4 trimethylation (H3K4me3) and gene transcription, which can regulate proliferation, apoptosis, and differentiation
  • regulates H3K27me3 and promoter DNA methylation via WT1 suggesting that WT1 protein plays an important, yet previously unappreciated role in regulating the function of the menin/PcG axis, H3K27 methylation, and DNA methylation, resulting in repression of gene transcription
  • pivotal role for menin in down-regulating PAX2 mRNA and protein expression
  • menin might serve as an important intracellular target of glucose to mediate the mitogenic effect that glucose exerts in pancreatic beta-cells
  • functions as an adaptor molecule to modulate gene expression by binding MLL at one site while also interacting with PSIP1 at a distinct surface
  • functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias
  • menin-dependent integration of H3 K9 methylation mightpotentially play an important role in preventing tumors
  • melanoma tumor suppressor that functions by stimulating the transcription of genes involved in homologous recombination-directed DNA repair
  • plays an important epigenetic role in promoting liver tumorigenesis
  • potential tumor-promoting function of menin in hepatocellular carcinoma
    • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • SMAD pathway
  • biological function of menin-WT1 regulated PAX2 signaling in endocrine neoplasia and renal disease
  • critical role of the MEN1-BACH2 pathway in regulating CD4 T-cell senescence and cytokine homeostasis
    • a component
  • component of MLL complexes
  • complex menin-CHEK1 on the damaged chromatin facilitates homologous recombination
  • MEN1 acts as a scaffold protein to assemble a MEN1–MLL–PSIP1 ternary complex to coordinate gene transcription and promote MLL-fusion-protein-induced leukaemogenesis
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacts with the JUN family transcription factor JUND and inhibits its transcriptional activity
  • inactivating MADH3 (SMAD3) by disrupting its DNA binding reduced menin expression antagonizes TGFB mediated inhibition of cell proliferation
  • NME1 (for tumor suppressor activity)
  • directly regulating CDKN1B and CDKN2C
  • interacting with MLL to regulate CDKN1B and CDKN2C (this interaction playing a central role in menin activity as a tumor suppressor)
  • interacting with FANCD2 for critical role in repair of DNA damage
  • interacting with DBF4
  • interacting with IQGAP1, reducing its interaction with GTP-Rac1 but increasing its E-Cadherin interaction
  • interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including ASH2L, RBBP5, and WDR5
  • directly interacting with CTNNB1 and carrying it out of the nucleus via nuclear-cytoplasmic shuttling
  • biochemical interaction between MEN1 and FOXN3 and the C-terminus of MEN1, which is frequently mutated in MEN1 patients, is necessary for this interaction
  • interacts with a large number of proteins involved in chromatin modification, transcription, cell cycle checkpoint and DNA repair
  • interacts with AKT1 (through interaction with AKT1, menin suppresses both AKT1-induced proliferation and antiapoptosis in nonendocrine and endocrine cells)
  • represses gene transcription of PAX2, which belongs to a family of genes that play a critical role in the formation of tissues and organs during embryonic development
  • specifically interact with WT1 (WT1 is a specific cofactor for menin-dependent and PcG-mediated H3K27 trimethylation and DNA hypermethylation for gene silencing)
  • proximal DNA elements within the GAST promoter mediate interactions between JUND, which induces GAST gene expression and MEN1, which suppresses JUND-mediated activation
  • interacts with MLL1, a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription
  • MEN1–JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription
  • functions as a transcriptional activator by tethering MLL complex to mediate histone H3 K4 methylation
  • binds to YAP1 promoter loci and up-regulates H3K4me3
  • MEN1 binding at the BACH2 locus and the BACH2 expression are decreased in the senescent CD4 T cells
    • cell & other
    REGULATION
    activated by NME1
    Other
  • phosphorylated by ATM or ATR upon DNA damage
    • ASSOCIATED DISORDERS
    corresponding disease(s) MEN1
    related resource Multiple Endocrine Neoplasia type 1 Mutation Database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   deletion    
    deleted in large cell neuroendocrine carcinoma
    tumoral   LOH    
    LOH in ependymomas (in progression)
    constitutional somatic mutation      
    mutated in isolated or familial primary hyperparathyrodism
    tumoral        
    isolated hyperparathyroid tumor, gastrinoma, insulinoma, bronchial carcinoid
    tumoral       loss of function
    in parathyroid, pituitary, islet cells tumor
    tumoral       gain of function
    in hepatocellular carcinoma
    tumoral   deletion    
    in parathyroid adenomas
    tumoral somatic mutation      
    somatic inactivating mutations n pancreatic neuroendocrine tumors
    tumoral     --over  
    in hepatocellular carcinoma and correlated with poor prognosis
    constitutional       gain of function
    during chronic liver injury plays a crucial role in promoting hepatocarcinogenesis
    Susceptibility to pituitary hyperplasia and tumorigenesis
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS