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FLASH GENE
Symbol KLF4 contributors: shn/pgu - updated : 24-01-2018
HGNC name Kruppel-like factor 4 (gut)
HGNC id 6348
Location 9q31.2      Physical location : 110.247.134 - 110.252.047
Synonym name
  • Krueppel-like factor 4
  • endothelial Kruppel-like zinc finger protein
  • epithelial zinc finger protein EZF
  • gut-enriched krueppel-like factor
  • Synonym symbol(s) RP11-150J11.1, EZF, GKLF, EVI162
    DNA
    TYPE functioning gene
    STRUCTURE 4.92 kb     5 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Map cen - D9S1784 - D9S17 - KLF4 - D9S1801 - D9S261 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    5 - 2949 50 479 - 1997 8702718
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon highly Homo sapiens
     intestinesmall intestine  moderately Homo sapiens
    Nervousbraindiencephalonhypothalamus   Rattus norvegicusFetal
    Reproductivemale systemtestis  highly Homo sapiens
    Respiratorylung   highly Homo sapiens
    Skin/Tegumentskin   highly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestivegoblet
    Nervousneuron Homo sapiens
    ReproductiveLeydig cell
    Reproductivespermatid
    cell lineage
  • monocyte-restricted and stage-specific pattern during myelopoiesis
  • vascular endothelial cells
  • cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • putative transactivation domain
  • a highly conserved 81 AA DNA binding domain
  • proline-rich N terminal domain
  • a repression domain
  • a SIM domain required for transactivation of target promoters in a SUMO-1-dependent manner, crucial for its anti-proliferative activity
  • three zinc finger domains of the C2H2 type at the C terminus
  • HOMOLOGY
    interspecies ortholog to Klf4, Mus musculus
    ortholog to Klf4, Rattus norvegicus
    ortholog to KLF4, Pan troglodytes
    intraspecies homolog to GKLF
    Homologene
    FAMILY
  • CACCC binding zinc finger protein
  • krueppel C2H2-type zinc-finger protein family
  • CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,chromatin/chromosome
    text localized to the nuclei of round spermatids during normal spermatogenesis stages II-IV
    basic FUNCTION
  • an essential mediator of p53 in the transcriptional induction of p21(WAF1/Cip1)
  • inhibitor of the cell cycle, acting both as a transcriptional activator and repressor
  • required for terminal differentiation of gobelet cells in the colon
  • essential for terminal differentiation of the epidermis and intestinal epithelium
  • a novel regulator of u-PAR expression that drives the synthesis of u-PAR in the luminal surface epithelial cells of the colon
  • may be a key effector of PDGFB and injury-induced phenotypic switching of smooth muscle cells
  • cooperating with POU5F1 and SOX2 to activate LEFTY1 expression and acting as a mediating factor that specifically binds to the proximal element of the LEFTY1 promoter
  • may be playing a role during spermiogenesis (altered subcellular localization of the protein during arrested spermiogenesis)
  • critical regulator in the transcriptional network controlling monocyte differentiation
  • can induce, in cooperation with Oct3/4, Sox2, and c-Myc, a variety of somatic cells into an embryonic stem cell-like state or induced pluripotent stem cells
  • involved in phenotypic modulation of vascular smooth muscle cells (VSMCS), and required for the expression of VSMC differentiation marker genes induced by all-trans retinoic acid
  • regulates both differentiation and growth that is likely fundamental to its tumor suppressor activity
  • playing an important role as a regulator of key signaling pathways that control macrophage activation
  • playing an important role in regulating the expression of IL10
  • epithelial cell-enriched, zinc finger-containing, transcription factor that has been widely investigated in both normal development and carcinogenesis
  • being a critical regulator in the transcriptional network controlling monocyte differentiation
  • suppresses tumorigenesis in gastrointestinal epithelium
  • pleiotropic zinc finger transcription factor that regulates genes being involved in differentiation and cell-cycle control
  • positively regulates human ghrelin expression via binding to a KLF-responsive region in the promoter
  • required for normal gastric epithelial proliferation and differentiation
  • possess both tumor suppressive and oncogenic functions in breast cancers
  • involved in mediating LIF signalling to the core circuitry but are not directly associated with the maintenance of pluripotency
  • implicated in vascular smooth muscle cell differentiation induced by all-trans retinoic acid (ATRA)
  • suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ESR1
  • transcriptional repressor of axon growth in retinal ganglion cells and other central nervous system neurons and regulates the regenerative capacity of central nervous system neurons
  • preventing ES cell differentiation by regulating NANOG gene expression
  • inhibits epithelial-to-mesenchymal transition in mammary epithelial cells through regulation of CDH1 gene expression and thus may have a metastasis suppressive role in breast cancer
  • plays a key role in late fetal and/or postnatal cardiac development
  • key role of KLF4 in the regulation of CDH5 expression at the level of the adherens junctions and in the acquisition of CDH5-mediated endothelial barrier function)
  • plays a key role in the maturation of TRH expression in hypothalamic neurons
  • transcription factor that plays an important role in cell differentiation, proliferation, and survival, especially in the context of cancers
  • plays a role in maintenance of high glycolytic metabolism by transcriptional activation of the PFKP gene in breast cancer cells
  • contributes to the stimulation of glycolytic metabolism in breast cancer cells by activating PFKP transcription
  • critical role of KLF4 in endothelial physiology
  • contributes potentially to high phosphate-induced conversion of SMCs into osteogenic cells
  • high phosphate-induced phenotypic switching of SMCs is mediated in part by KLF4
  • regulated the transcription of osteogenic genes in SMCs
  • having likely dual roles during the vascular calcification process: not only decreasing expression of SMC differentiation marker genes, but also inducing osteogenic genes
  • KLF4 is expressed in neural stem cells and controls axonal regeneration
  • precise regulation of KLF4 expression is critical to neuronal differentiation and migration during the formation of a cerebral cortex
  • is a zinc finger-containing transcription factor that regulates multiple biological functions, including proliferation and differentiation
  • KLF4 has a direct role in governing the morphological change of migrating neurons
  • balance between ZEB2 and KLF4 protein levels is important for the modulation of CDH1 expression
  • may serve as an essential regulator of endothelial barrier function
  • .ADORA2B is a regulator of adipocyte differentiation and the ADORA2B-KLF4 axis is a potentially significant modulator of adipose biology
  • KLF4 is a critical regulator of monocyte differentiation and macrophage polarization, and it also plays an important role in several vascular diseases, including atherosclerosis
  • novel function for KLF4 in regulating the MAP2K7 pathway in T-ALL cells, which can be targeted to eradicate leukemia-initiating cells in T-ALL patients
  • novel function of DDX3X in regulating expression and downstream functions of KLF4, a master negative regulator of the cell cycle
  • CELLULAR PROCESS cell life, differentiation
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • with HTATIP and HDAC7 form a complex and cooperatively repress the histidine decarboxylase (HDC) promoter activity
  • INTERACTION
    DNA
  • binds to the promoter-enhancer regions of smooth muscle cell differentiation marker genes
  • binds to GC-rich DNA with a consensus binding sequence of CACCC
  • binding to the promoter of NANOG and regulates its expression
  • binding to the GC-rich/E box region of the promoter
  • promoter region of the Gata4 gene
  • RNA
    small molecule
    protein
  • a negative regulator of the CYP1A1 promoter in a BTE-dependent fashion
  • p300/CBP
  • stimulate NOS2 expression in macrophages
  • transcription factor Zf9, Zf9
  • NF-kappaB family member p65 (RELA)
  • ELK1, member of ETS oncogene family, ELK1 andhistone deacetylase 5, HDAC5
  • GHRL (increases ghrelin transcription in the stomach, which may play an important role in the tissue-specific or fasting-mediated expression of ghrelin)
  • binds directly to the C/EBPbeta (CEBPB) promoter and, together with EGR2, cooperatively transactivates a CEBPB reporter
  • he DNA-binding region of ERalpha
  • TBP1
  • physically interacts with SUMO1 in a region that matches an acidic and hydrophobic residue-rich SUMO-interacting motif (SIM) consensus
  • interact with EP300 through the region that is homologous to EKLFTAD2
  • IFITM3 is a direct transcriptional target of KLF4 and dysregulated KLF4 expression leads to aberrant IFITM3 expression, thus contributing to colon cancer progression and metastasis
  • ASS1 is a key regulatory role of KLF4 in the endothelial ASS1 expression and NO production in response to laminar shear stress
  • KLF4 stimulates and KLF15 inhibits MCM2 transcription through modulating histone acetylation and methylation, and thereby RNA Pol II binding
  • increased the transcriptional activity of the osteopontin promoters containing two consensus KLF4 binding sites
  • overactivation of STAT3 indeed plays a role in the KLF4-induced radial migration defect
  • chromatin regulators EP300, KDM5A, KDM6A and KDM6B cooperate with KLF4 in promoting the transcription of POU5F1
  • CDH1 expression is repressed by ZEB2 while it is induced by KLF4
  • can bind to and activate the IL6 promoter at specific binding sites, and has a role in the chromatin remodeling of the IL6 promoter in that cells deficient in KLF4 exhibited a relative hypoacetylation
  • regulates blood-tumor barrier permeability via TJP1, OCLN and CLDN5
  • KLF4 expression resulted from the codependent and synergistic action of NANOG and STAT3 in embryonic stem cells and during initiation of reprogramming
  • KLF4 is a regulator of cardiac hypertrophy by modulating the expression and the activity of MYOCD
  • BAALC blocks ERK-mediated monocytic differentiation of AML cells by trapping KLF4 in the cytoplasm and inhibiting its function in the nucleus
  • robust synchronized induction of KLF4 and APOE expression during differentiation of monocytes to macrophages, and KLF4 up-regulates APOE gene in a dose-dependent manner
  • KLF4 represses the gene encoding the kinase MAP2K7
  • KLF4 is important for regulating the expression of NOS2 by TNF in human synoviocytes
  • aberrant SF3B4 overexpression altered the progress of splicing progress of the tumor suppressor gene, KLF4, and resulted in non-functional skipped exon transcripts, contributing to liver tumorigenesis
  • cell & other
    REGULATION
    induced by lipopolysaccharide in macrophages
    HDL (induction of KLF4 by HDL could promote the expression of SCARB1, resulting from the binding to putative KLF4 binding element on the promoter of SCARB1)
    Other regulated by all-trans retinoic acid (increases KLF4 acetylation and its DNA-binding activity via inducing HDAC2 phosphorylation and dissociation from KLF4)
    transactivated by Zf9
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in colorectal cancer
    tumoral     --low  
    in gastric and colon cancers
    tumoral     --over  
    in more than 70p100 of breast cancers
    tumoral       loss of function
    inactivated by DNA methylation in children with T-cell acute lymphoblastic leukemia (T-ALL
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyacquired 
    manipulating KLF4 or multiple KLF genes may be a useful strategy to add to existing approaches to increase the intrinsic regenerative capacity of mature CNS neurons damaged by injury or disease
    cancerreproductivebreast
    KLF4 and PFKP may be sensitive targets in designing selective breast cancer chemotherapy
    miscelleaneousvascular 
    control of KLF4 might be a novel therapeutic target for vascular calcification
    ANIMAL & CELL MODELS
    Klf4-/- mice die shortly after birth due to loss of skin barrier function, as measured by penetration of external dyes and rapid loss of body fluids
  • colon cells from KLF4 null mice showed a dramatic reduction in u-PAR protein compared with wild-type mice
  • tissue-specific ablation of Klf4 in mouse stomach results in increased proliferation and altered differentiation of the gastric epithelia
  • mice lacking the transcription factor Klf4 have a significant upregulation of the gap junction protein connexin 26 leading to a severe defect in epidermal barrier acquisition
  • conditional knock-out of Klf4 results in abnormal corneal epithelium and lack of goblet cells in the conjunctiva
  • retinal ganglion cells lacking KLF4 showed increased axon growth both in vitro and after optic nerve injury in vivo
  • lack of Klf4 in the mouse heart result in the reduction in expression of multiple cardiac genes, including Gata4