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FLASH GENE

Symbol

MEN1

contributors: mct/pgu - updated : 12-05-2013

HGNC name	multiple endocrine neoplasia I
HGNC id	7010

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000244 10 - 2785 NP_000235 67.8 615 - 1997 9253601 isoform 1 NM_130800 10 splicing 2748 NP_570712 67.8 615 - 1997 9253601 variant e1B, differing by its 5'utr isoform 1 NM_130801 10 splicing 2736 NP_570713 67.8 615 - 1997 9253601 variant e1C, differing by its 5'utr isoform 1 NM_130802 10 splicing 3172 NP_570714 67.8 615 - 1997 9253601 variant e1D, differing by its 5'utr isoform 1 NM_130803 10 splicing 3179 NP_570715 67.8 615 - 1997 9253601 variant e1E, differing by its 5'utr isoform 1 NM_130799 10 splicing 2770 NP_570711 67.3 610 - 1997 9253601 isoform 2 NM_130804 11 splicing 3051 NP_570716 67.8 615 - 1997 9253601 variant e1F1, isoform 1

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive salivary gland       highly Lymphoid/Immune lymph node       highly Reproductive female system uterus     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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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