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FLASH GENE
Symbol ZEB1 contributors: mct/ - updated : 04-02-2017
HGNC name zinc finger E-box binding homeobox 1
HGNC id 11642
Corresponding disease
FECD6 corneal dystrophy, Fuchs endothelial 6
PPCD3 posterior polymorphous corneal dystrophy 3
Location 10p11.22      Physical location : 31.608.100 - 31.818.741
Synonym name
  • zinc finger homeodomain enhancer-binding protein
  • transcription factor 8 (Nil-2-a)
  • transcription factor 8 (represses interleukin 2 expression)
  • negative regulator of IL2
  • transcription factor 8
  • delta-crystallin enhancer binding factor 1
  • NIL-2-A zinc finger protein
  • Synonym symbol(s) BZP, ZEB, TCF8, AREB6, ZFHEP, NIL-2A, ZFHX1A , NIL-2-A, delta EF1, Zfhep, Zfhx1a, DELTAEF1
    DNA
    TYPE functioning gene
    STRUCTURE 210.64 kb     9 Exon(s)
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure
  • both TWIST1 and ETS1 bind to the ZEB1 promoter although to different elements: whereas ETS1 interacts with the proximal promoter, Twist does it with a 700-bp sequence upstream of the transcription start site
  • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 - 6278 - 1108 - 2012 22652173
  • able to repress expression of its own gene by binding to one of these E2-box sites
  • 9 - 5998 - 1124 - 2012 22652173
  • N-terminal-deleted isoform
  • competing for binding and acting as a dominant negative of ZFHX1A-1, antagonizing auto-repression of the gene
  • 8 - 5938 - 1104 - 2012 22652173
    9 - 6275 - 1107 - 2012 22652173
    8 - 5797 - 1057 - 2012 22652173
    9 - 6001 - 1125 - 2012 22652173
    EXPRESSION
    Rna function mRNA was detected in the late stages of T-cell development
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestivemouth   highly
    Reproductivefemale systemplacenta    Homo sapiens
    Respiratoryrespiratory tracttrachea  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumcardiac  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo
    Text strongly expressed in endothelial and mesenchymal cells of the villous structures during the last two trimesters, suggesting that it plays a role in the development of placental blood vessels
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal region comprising the SMARCA4-interacting domain
  • seven C2H2 zinc finger domains arranged in two widely separated cluster at opposite ends of the molecule
  • binds to the E-box consensus sequence, CACCTGT, through either the N- or the C-terminal zinc finger cluster,
  • a glutamic acid-rich region at the C terminus and C-terminal region spanning amino acids 1011 to 1124 with a conventional acidic activation domain
  • an homeobox DNA-binding domain
  • HOMOLOGY
    interspecies homolog to murine Zfhx1a
    homolog to C.elegans 157c7.1b
    Homologene
    FAMILY
  • delta EF1/ZFH-1 family of two zinc finger
  • CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,chromatin/chromosome
    text
  • ZEB1 interacts with hepatoma-derived growth factor (HDGF) and co-localizes in the nucleus
  • basic FUNCTION
  • inhibiting interleukin-2 expression in T-lymphocytes
  • repressing or activating specific target genes depending on the differential recruitment of co-repressor or co-activators
  • transcriptional repression of PKP3 by ZEB1 contributes to ZEB1-mediated disintegration of intercellular adhesion and epithelial to mesenchymal transition
  • potent transcriptional repressor of E-cadherin directly repressing the expression of PKP3 in invasive cancer cells
  • induces the disassembly of desmosomal structures that normally provide epithelial sheets with additional adhesive strength and resistance to mechanical stress
  • involved in smooth muscle differentiation, neurodifferentiation, skeletal patterning, lymphopoiesis and cancer metastasis
  • represents a key player in pathologic epithelial to mesenchymal transition associated with tumour progression
  • playing a role in epithelial to mesenchymal transitions associated with aggressive tumors
  • EMT-inducing transcriptional repressor, that promotes colorectal cancer cell metastasis and loss of cell polarity
  • crucial promoter of malignant tumor progression
  • induces an epithelial-to-mesenchymal transition and confers a metastatic phenotype on carcinomas by repressing the E-cadherin gene at the transcriptional level
  • ZEB1/SMARCA4 is a new transcriptional mechanism regulating E-cadherin (CDH1) expression and epithelial-to-mesenchymal transdifferentiation that may be involved during the initial stages of tumor invasion
  • forming a repressive complex with CTBP1 protein binding to the distal promoter element of BCL6 and controlling its expression
  • expression of ZEB1 during the late stages of T-cell differentiation is necessary for enhancing the growth-inhibitory effect of TGF-B1 on CD4+ T cells
  • may have a role in enhancing TGF-beta1 signaling by binding not only to SMAD3 but also to SMAD7 in the nucleus
  • may have important roles in the regulation of TGF-beta1 signaling, and both ZEB1 downregulation and SMAD7 overexpression may be important molecular events that contribute to resistance to TGF-B1 signaling in adult T-cell leukemia/lymphoma
  • required for several NTRK2-induced effects in vitro and in vivo, including metastasis
  • SNAI2 and ZEB1 are important repressors of E-cadherin, contributing to epithelial-mesenchymal transition (EMT) in primary epithelial cancers
  • is an effector of CTNNB1/TCF4 signaling in epithelial-to-mesenchymal transition (EMT) and tumor progression
  • its expression is key in the initiation and/or maintenance of the EMT process
  • acts also as an effector of this signaling pathway in regulating genes associated to tumor invasiveness
  • may participate in STAT3-induced cell invasion and E-cadherin down-regulation in colorectal cancer cells
  • may mediate STAT3-induced down-regulation of CDH1 via directly inhibiting transcriptional activity of the CDH1 promoter in colorectal cancer
  • transcriptional repressor promoting metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors
  • drives prometastatic actin cytoskeletal remodeling by downregulating MIR34a expression
  • important regulator of the temporal pattern of gene expression controlling muscle differentiation
  • is a typical transcription inhibitory factor of CDH1, playing a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • ZEB1/SMARCA4 is a new transcriptional mechanism in the repression of E-cadherin during epithelial-mesenchymal transition and tumor progression
  • INTERACTION
    DNA
  • binding to a negative regulatory domain 100 nucleotides upstream of the IL2 transcription start site
  • RNA
    small molecule metal binding,
  • Zn2+
  • protein
  • interacting with VDR and SNAI1 in colorectal cancer (loss of VDR and TCF8 and presence of SNAI1 is predictor of poor clinical prognosis)
  • associates with two conserved E-box elements in the PKP3 promoter and partially represses the activity of corresponding PKP3 promoter fragments
  • interact with E-box elements in the proximal promoter region of target genes such as E-cadherin
  • interacting with CDH13 (represses CDH13 expression and thus increases the invasive activity of gallbladder cancer)
  • binds to receptor-regulated SMAD2/3 and synergizes with SMAD-mediated transcriptional activation
  • interacting with LLGL2 (suppresses the expression of cell polarity factors, in particular of LLGL2, which we found reduced in colorectal and breast cancers)
  • interacting with NEUROD2 (induces transcription of neuronal genes and ZEB1, which in turn de-represses neuronal differentiation by down-regulating REST, and suppresses competing myogenic fate)
  • interacts with the SWI/SNF chromatin-remodeling protein BRG1 to regulate E-cadherin independently of CTBP1, its traditional co-repressor
  • SNAI1 controls ZEB1 expression at multiple levels and acts cooperatively with TWIST1 in the ZEB1 gene transcription induction
  • required for NTRK2-induced EMT in epithelial cells
  • interacting with WISP3 (WISP3 decreases ZEB1-mediated EMT and invasion by attenuation of IGF1 receptor signaling in breast cancer)
  • GAB2 inhibits CDH1 expression and enhances the expression of ZEB1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), and cell migration and invasion through the activation of the PI3K pathway
  • CTNNB1/TCF4 binds directly to the ZEB1 promoter and activates its transcription
  • in colorectal carcinoma cells ZEB1 directly activates LAMC2 expression, although these results do not exclude the possibility of concurrent indirect regulation via MIR200
  • STAT3 may directly mediate EMT(epithelial-mesenchymal transition) progression and regulate ZEB1 expression in colorectal cancer
  • ETV5 modulated ZEB1 expression and CDH1 repression leading to a complete reorganization of cell-cell and cell-substrate contacts
  • binds to an E-box sequence in the AR gene promoter, and physically interacts with AR in human foreskin cells
  • SLC2A3 is a transcriptional target of ZEB1
  • VANGL1 induced the expression of the epithelial-mesenchymal transition (EMT) markers (N-cadherin, ZEB1, ZEB2, SNAI1 and SNAI2) as well as the glioma stemness markers (CD133, ALDH1 and EPHB1)
  • OVOL2 acts as a direct transcriptional repressor of the established PPCD3-associated gene ZEB1
  • PTBP3 is a regulator of EMT that acts by governing expression of ZEB1, and leading to an oncogenic function of PTBP3
  • GRHL2 is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1
  • ZEB1 is a transcriptional activator of SOX8 that enhanced SOX8 expression by binding to its promoter
  • ZEB1 represses neural differentiation and cooperates with CTBP2 to dynamically regulate cell migration during neocortex development
  • interaction between ZEB1 and CTBP2 in the embryonic cerebral cortex is required for ZEB1 to elicit its effect on the multipolar-to-bipolar transition, but not its suppression of NEUROD1
  • ZEB1 positively correlates with HDGF expression, and co-expression of ZEB1 and HDGF promotes the pathogenesis of endometrial carcinoma (EC)
  • cell & other
  • contrary to MYOD1, ZEB1 binds to G/C-centered E-boxes in muscle differentiation genes at the myoblast stage but not in myotubes
  • REGULATION
    activated by SNAI2 (transcriptional activation of ZEB1 by SNAI2 leads to cooperative regulation of the epithelial-mesenchymal transition-like phenotype in melanoma)
    directly activated by CTNNB1/TCF4
    induced by SPRY2 (induces the epithelial-to-mesenchymal transition gene ZEB1
    POU2F1 (POU2F1 induced the expression of TWIST1, SNAI1, SNAI2 and ZEB1 genes which are involved in the regulation of epithelial-to-mesenchymal transition (EMT)
    repressed by cofactor NC2
    Other regulated by ZFHX1A-2 (transcriptional regulation) and by changes of phosphorylation
    regulated by both estrogen and progesterone receptors
    ASSOCIATED DISORDERS
    corresponding disease(s) PPCD3 , FECD6
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in colorectal cancer with polyps
    tumoral     --over  
    in colorectal cancer, at the invasive front accompanied by downregulation of PKP3 protein levels and loss of intercellular adhesion
    constitutional       gain of function
    in the myometrium and stroma during the secretory stage of the menstrual cycle (is not expressed in the normal endometrial epithelium)
    tumoral     --over  
    in malignant tumors derived from the myometrium (leiomyosarcomas), and in tumor-associated stroma of low-grade endometrioid adenocarcinomas
    tumoral     --other  
    aberrantly expressed in the tumor epithelial cells of aggressive endometrial cancers
    tumoral     --other  
    in E-cadherin-negative carcinoma cell lines and is in part responsible for enhanced motility of bladder cancer cells
    tumoral     --low  
    with SMAD7 overexpression contribute to resistance to TGF-beta1-mediated growth suppression in ATLL(adult T-cell leukemia/lymphoma)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker important diagnostic predictor in colorectal carcinoma
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestivecolon
    potential therapeutic target in colorectal carcinoma
    cancerreproductivebreast
    ZEB1-SOX8 regulatory axis could be a promising therapeutic target for triple-negative breast cancer (TNBC)
    ANIMAL & CELL MODELS