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KLF4 (Kruppel-like factor 4 (gut))

Identity

Other namesGKLF
EZF
HGNC (Hugo) KLF4
LocusID (NCBI) 9314
Location 9q31.2
Location_base_pair Starts at 110247133 and ends at 110252047 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  The structure of the murine KLF4 gene. The four exons of the murine GKLF gene are identified by Roman numerals. The translated region or open reading frame is depicted in black. The locations of restriction sites for several endonucleases are labeled: Nc, NcoI; N, NotI; K, KpnI; H, HindIII; Xh, XhoI; Sm, SmaI; Xb, XbaI; Bg, BglII; B, BamHI.
Description A full-length mouse cDNA clone encoding KLF4 was initially isolated from a NIH3T3 cDNA library by reduced stringency screening with a DNA probe containing the zinc finger region of an immediate early gene product, Zif268 or Egr1. A distinct feature of the KLF4 gene is the highly GC-rich nature of the sequence near its 5'-end. Thus, the G+C content of the 1000 nt 5'-flanking region is 67% and that of the 5'-untranslated region is 63%. Moreover, the bulk of the GC residues are concentrated in the region between nt -600 and +300 of the gene where the G+C content is 82%. The gene has four exons, each containing a portion of the translated region.
Transcription The open-reading frame of the Klf4 gene encodes a polypeptide of 483 amino acids with a predicted molecular weight of 53 kDa. The entire polypeptide sequence of Klf4 with the exception of the first amino acid is encoded by exons 2, 3 and 4.

Protein

Description KLF4 encodes a polypeptide of 483 aa and similar to KLFs, contains three Kruppel-type zinc fingers in the very C-terminal end. The region immediately N terminal to the three zinc fingers is a 20-aa peptide containing a cluster of basic aa residues, which is essential for the nuclear localization of the protein.
Expression KLF4 is a nuclear protein whose cellular address depends on two nuclear localization signals. Expression of the KLF4 gene is developmentally regulated, with a higher level of expression occurring toward the later stage of fetal development. In adults, KLF4 is highly enriched in epithelial tissues, including the skin, lung, and intestine. In the intestinal tract, KLF4 is predominantly present in the terminally differentiated, postmitotic epithelial cells lining the villus border of the small intestine and the upper crypt region of the large intestine. In cultured cells, the level of KLF4 mRNA is associated with the growth-arrested state in a manner similar to that observed in the intestinal epithelium. Expression of KLF4 can also be found in a select number of other organs including the lung, testis, skin and thymus, and in vascular endothelial cells.
 
Localisation KLF4 is a nuclear protein that contains two potent nuclear localization signals (NLSs), one within the three zinc fingers and the other in a cluster of basic amino acids immediately adjacent to the first zinc finger. These two NLSs define a subfamily of three closely related KLFs: KLF1, KLF2, and KLF4.
Function KLF4 binds to DNA sequence elements that are GC-rich. A consensus DNA binding sequence was empirically determined and is present in the promoters of many genes, including the CACCC element and the basic transcription element (BTE). KLF4 inhibits the promoter of the cytochrome P-450IA1 ( CYP1A1 ) gene in a BTE-dependent manner.
In cultured cells, the level of KLF4 mRNA is associated with the growth-arrested state in a manner similar to that observed in the intestinal epithelium. Forced expression of KLF4 in cultured cells results in the inhibition of DNA synthesis. The induction of KLF4 is also correlated with an increase in the level of p21WAF1/CIP1, a critical checkpoint protein that inhibits cell cycle progression and is essential in mediating the cell cycle arrest at both the G1/S and G2/M boundaries. Importantly, KLF4 is essential in the induction of expression of the p21WAF1/CIP1 gene in response to DNA damage by binding to a specific cis-DNA element in the p21WAF1/CIP1 proximal promoter to activate p21WAF1/CIP1 expression. cDNA microarray analysis of the transcriptional profiles of KLF4 demonstrates that KLF4 inhibits the cell cycle by coordinately regulating expression of numerous cell cycle regulatory genes.
KLF4 mediates the cell cycle checkpoint function of the tumor suppressor p53 suggesting that it may itself act as a tumor suppressor. Its mRNA are reduced in intestinal adenomas of ApcMin/+ mice and colonic adenomas of patients with familial adenomatous polyposis (FAP) when compared with surrounding normal tissues. Conversely, overexpression of KLF4 in the human colon cancer cell line RKO, which does not express endogenous KLF4, results in reduced tumorigenesis in vitro and in vivo. KLF4 plays a role in mediating the tumor-suppressive function of APC. KLF4 can down-regulate the level of beta-catenin and can bind directly to the transcriptional activation domain of beta-catenin to inhibit beta-catenin-mediated transcription. KLF4 haploinsufficiency in ApcMin/+ mice lead to significantly more intestinal adenomas than ApcMin/+ mice alone.
In vivo, KLF4 is required for goblet cell differentiation in the intestine and eye conjuctiva. KLF4 has been shown to be down-regulated by Notch pathway and is important in maintaining the normal skin barrier.
Induction of KLF4 significantly reduces the percentage of apoptotic cells following g-irradiation. Upregulation of KLF4 also inhibits expression of the gene encoding the pro-apoptotic protein Bax following DNA damage.
Taken together, these studies place KLF4 in an interesting and important position between the Wnt and Notch signaling pathways, both of which are crucial for intestinal tumorigenesis. Additional studies are likely to further reveal the exact mechanism by which KLF4 mediates the crosstalk functions of these two key pathways in CRC.
 
Homology KLF4 belongs to the SP1 / KLF transcription factor family that is highly conserved among species (from Drosophila to human). Mouse KLF4 and is 90% identical to human KLF4. The carboxyl terminus of KLF4 contains three C2H2-zinc fingers that are most closely related to another member of the family, KLF2.

Mutations

Note A number of colon cancer cell lines contain point mutations in the coding region of KLF4 that resulted in a diminished ability to activate the p21WAF1/Cip1 promoter. Also there is evidence for LOH of the KLF4 locus and of hypermethylation of the 5'-UTR in resected CRC specimens and colon cancer cell lines.

Implicated in

Entity Colorectal Cancer (CRC)
Disease The relevance of KLF4 in the pathogenesis of human CRC is demonstrated by a significant reduction of KLF4 mRNA levels in colorectal adenoma and adenocarcinoma compared with matched normal colonic tissues. There is also evidence for LOH in a subset of CRC and in a panel of CRC cell lines. Moreover, the 5-untranslated region of the KLF4 gene is found to be hypermethylated in a subset of CRC. Lastly, several point mutations are identified in KLF4 that result in a diminished ability to activate the p21WAF1/CIP1 promoter in some of the CRC cell lines. These studies suggest that KLF4 is a tumor suppressor, at least in a fraction of patients with CRC. Recent studies demonstrating that KLF4 is involved in maintaining centrosome duplication and thus genomic stability further illustrate the mechanism by which KLF4 may be involved in tumor suppression.
  
Entity Goblet cells hypoplasia.
Disease Mice homozygous for a null mutation in the Klf4 gene die shortly after birth, for unknown reasons. Immediately following birth, Klf4-/- mice have a 90% reduction in the number of goblet cells in their colon, show abnormal expression of the goblet cell-specific marker Muc2, and have abnormal goblet cell morphology.
  
Entity Gastric cancer
Disease Mutational analysis indicates that the KLF4 gene is subject to deletion, mutation and methylation silencing in a significant proportion of colon and gastric cancers. Conditional Klf4-knockout mouse specific for the gastric epithelium, loss of Klf4 results in increased proliferation and differentiation in the stomach, culminating in precancerous changes altered.
  
Entity Breast cancer
Disease KLF4 levels are elevated in up to 70% of mammary carcinomas.
Prognosis Nuclear localization of KLF4 is associated with an aggressive phenotype in early stage breast cancer.
Oncogenesis Oncogene.
  
Entity Dysplastic oral squamous-cell carcinomas
Disease KLF4 levels are elevated in oropharyngial dysplastic squamous-cell carcinomas.
  
Entity Squamous cell carcinoma
Disease Ectopic expression of KLF4 in basal keratinocytes of transgenic mice results in dysplastic lesions that resemble squamous cell carcinoma in situ.
  

External links

Nomenclature
HGNC (Hugo)KLF4   6348
Cards
AtlasKLF4ID44316ch9q31
Entrez_Gene (NCBI)KLF4  9314  Kruppel-like factor 4 (gut)
GeneCards (Weizmann)KLF4
Ensembl (Hinxton)ENSG00000136826 [Gene_View]  chr9:110247133-110252047 [Contig_View]  KLF4 [Vega]
ICGC DataPortalENSG00000136826
cBioPortalKLF4
AceView (NCBI)KLF4
Genatlas (Paris)KLF4
WikiGenes9314
SOURCE (Princeton)NM_004235
Genomic and cartography
GoldenPath (UCSC)KLF4  -  9q31.2   chr9:110247133-110252047 -  9q31   [Description]    (hg19-Feb_2009)
EnsemblKLF4 - 9q31 [CytoView]
Mapping of homologs : NCBIKLF4 [Mapview]
OMIM602253   
Gene and transcription
Genbank (Entrez)AF022184 AF105036 AK095134 AK095894 AK313489
RefSeq transcript (Entrez)NM_004235
RefSeq genomic (Entrez)AC_000141 NC_000009 NC_018920 NT_008470 NW_001839236 NW_004929366
Consensus coding sequences : CCDS (NCBI)KLF4
Cluster EST : UnigeneHs.376206 [ NCBI ]
CGAP (NCI)Hs.376206
Alternative Splicing : Fast-db (Paris)GSHG0031046
Alternative Splicing GalleryENSG00000136826
Gene ExpressionKLF4 [ NCBI-GEO ]     KLF4 [ SEEK ]   KLF4 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO43474 (Uniprot)
NextProtO43474  [Medical]
With graphics : InterProO43474
Splice isoforms : SwissVarO43474 (Swissvar)
Domaine pattern : Prosite (Expaxy)ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (EBI)Znf_C2H2 [organisation]   Znf_C2H2-like [organisation]   Znf_C2H2/integrase_DNA-bd [organisation]  
Related proteins : CluSTrO43474
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Domain families : Smart (EMBL)ZnF_C2H2 (SM00355)  
DMDM Disease mutations9314
Blocks (Seattle)O43474
Human Protein AtlasENSG00000136826 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO43474
IPIIPI00012531   IPI00167069   IPI00643479   IPI01014408   IPI00927339   IPI00927550   
Protein Interaction databases
DIP (DOE-UCLA)O43474
IntAct (EBI)O43474
FunCoupENSG00000136826
BioGRIDKLF4
InParanoidO43474
Interologous Interaction database O43474
IntegromeDBKLF4
STRING (EMBL)KLF4
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  core promoter proximal region sequence-specific DNA binding  sequence-specific DNA binding transcription factor recruiting transcription factor activity  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  RNA polymerase II transcription factor binding  RNA polymerase II transcription factor binding  RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription  double-stranded DNA binding  sequence-specific DNA binding transcription factor activity  protein binding  nucleus  transcription factor complex  nucleolus  transcription from RNA polymerase II promoter  mesodermal cell fate determination  zinc ion binding  negative regulation of cell proliferation  epidermal cell differentiation  negative regulation of phosphatidylinositol 3-kinase signaling  negative regulation of muscle hyperplasia  stem cell maintenance  post-embryonic camera-type eye development  negative regulation of NF-kappaB transcription factor activity  positive regulation of cellular protein metabolic process  response to retinoic acid  negative regulation of heterotypic cell-cell adhesion  phosphatidylinositol 3-kinase regulator activity  post-embryonic hemopoiesis  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  regulation of phosphatidylinositol 3-kinase activity  transcription regulatory region DNA binding  negative regulation of interleukin-8 biosynthetic process  positive regulation of nitric oxide biosynthetic process  fat cell differentiation  regulation of cell differentiation  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  positive regulation of hemoglobin biosynthetic process  negative regulation of smooth muscle cell proliferation  epidermis morphogenesis  negative regulation of inflammatory response  positive regulation of protein metabolic process  negative regulation of protein kinase B signaling  negative regulation of response to cytokine stimulus  cellular response to hydrogen peroxide  negative regulation of ERK1 and ERK2 cascade  cellular response to growth factor stimulus  cellular response to cycloheximide  cellular response to laminar fluid shear stress  negative regulation of cell migration involved in sprouting angiogenesis  cellular response to peptide  negative regulation of chemokine (C-X-C motif) ligand 2 production  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  core promoter proximal region sequence-specific DNA binding  sequence-specific DNA binding transcription factor recruiting transcription factor activity  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  RNA polymerase II transcription factor binding  RNA polymerase II transcription factor binding  RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription  double-stranded DNA binding  sequence-specific DNA binding transcription factor activity  protein binding  nucleus  transcription factor complex  nucleolus  transcription from RNA polymerase II promoter  mesodermal cell fate determination  zinc ion binding  negative regulation of cell proliferation  epidermal cell differentiation  negative regulation of phosphatidylinositol 3-kinase signaling  negative regulation of muscle hyperplasia  stem cell maintenance  post-embryonic camera-type eye development  negative regulation of NF-kappaB transcription factor activity  positive regulation of cellular protein metabolic process  response to retinoic acid  negative regulation of heterotypic cell-cell adhesion  phosphatidylinositol 3-kinase regulator activity  post-embryonic hemopoiesis  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  regulation of phosphatidylinositol 3-kinase activity  transcription regulatory region DNA binding  negative regulation of interleukin-8 biosynthetic process  positive regulation of nitric oxide biosynthetic process  fat cell differentiation  regulation of cell differentiation  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  positive regulation of hemoglobin biosynthetic process  negative regulation of smooth muscle cell proliferation  epidermis morphogenesis  negative regulation of inflammatory response  positive regulation of protein metabolic process  negative regulation of protein kinase B signaling  negative regulation of response to cytokine stimulus  cellular response to hydrogen peroxide  negative regulation of ERK1 and ERK2 cascade  cellular response to growth factor stimulus  cellular response to cycloheximide  cellular response to laminar fluid shear stress  negative regulation of cell migration involved in sprouting angiogenesis  cellular response to peptide  negative regulation of chemokine (C-X-C motif) ligand 2 production  
Protein Interaction DatabaseKLF4
Wikipedia pathwaysKLF4
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)KLF4
snp3D : Map Gene to Disease9314
SNP (GeneSNP Utah)KLF4
SNP : HGBaseKLF4
Genetic variants : HAPMAPKLF4
Exome VariantKLF4
1000_GenomesKLF4 
ICGC programENSG00000136826 
Cancer Gene: CensusKLF4 
Somatic Mutations in Cancer : COSMICKLF4 
CONAN: Copy Number AnalysisKLF4 
Mutations and Diseases : HGMDKLF4
Mutations and Diseases : intOGenKLF4
Genomic VariantsKLF4  KLF4 [DGVbeta]
dbVarKLF4
ClinVarKLF4
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM602253   
MedgenKLF4
GENETestsKLF4
Disease Genetic AssociationKLF4
Huge Navigator KLF4 [HugePedia]  KLF4 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneKLF4
Homology/Alignments : Family Browser (UCSC)KLF4
Phylogenetic Trees/Animal Genes : TreeFamKLF4
Chemical/Protein Interactions : CTD9314
Chemical/Pharm GKB GenePA30138
Clinical trialKLF4
Cancer Resource (Charite)ENSG00000136826
Other databases
Probes
Litterature
PubMed193 Pubmed reference(s) in Entrez
CoreMineKLF4
iHOPKLF4
OncoSearchKLF4

Bibliography

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Human EZF, a Kruppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains.
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The gut-enriched Kruppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion.
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PMID 9651398
 
Characterization of the structure and regulation of the murine gene encoding gut-enriched Kruppel-like factor (Kruppel-like factor 4).
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PMID 10556311
 
GKLF in thymus epithelium as a developmentally regulated element of thymocyte-stroma cross-talk.
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PMID 10330488
 
Klf4 is a transcription factor required for establishing the barrier function of the skin.
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Decreased expression of the gut-enriched Kruppel-like factor gene in intestinal adenomas of multiple intestinal neoplasia mice and in colonic adenomas of familial adenomatous polyposis patients.
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The biology of the mammalian Kruppel-like family of transcription factors.
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Increase of GKLF messenger RNA and protein expression during progression of breast cancer.
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Cancer Res. 2000 Nov 15;60(22):6488-95.
PMID 11103818
 
Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation.
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Am J Physiol Gastrointest Liver Physiol. 2000 Oct;279(4):G806-14.
PMID 11005769
 
The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/CIP1 promoter.
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Kruppel-like factor 4 (gut-enriched Kruppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle.
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The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon.
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Transcriptional profiling of Kruppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation.
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Overexpression of Kruppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity.
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Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage.
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Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer.
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Requirement of Kruppel-like factor 4 in preventing entry into mitosis following DNA damage.
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Identification of Kruppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer.
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Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia.
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Kruppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation.
Ghaleb AM, Nandan MO, Chanchevalap S, Dalton WB, Hisamuddin IM, Yang VW.
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The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a contextdependent oncogene.
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PMID 16244670
 
Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.
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Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression.
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Kruppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage.
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PMID 15806166
 
Novel cross talk of Kruppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression.
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PMID 16507986
 
WNT signaling in the normal intestine and colorectal cancer.
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PMID 17127311
 
Kruppel-like factor 4 exhibits anti-apoptotic activity following gamma-radiation-induced DNA damage.
Ghaleb AM, Katz JP, Kaestner KH, Du JX, Yang VW.
Oncogene. 2007 Apr 5;26(16):2365-73. Epub 2006 Oct 2.
PMID 17016435
 
Haploinsufficiency of Kruppel-Like Factor 4 Promotes Adenomatous Polyposis Coli-Dependent Intestinal Tumorigenesis.
Ghaleb AM, McConnell BB, Nandan MO, Katz JP, Kaestner KH, Yang VW.
Cancer Res. 2007 Aug 1;67(15):7147-54.
PMID 17671182
 
The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology.
McConnell BB, Ghaleb AM, Nandan MO, Vincent W. Yang.
Bioessays. 2007 Jun;29(6):549-57. (REVIEW)
PMID 17508399
 
The Pathobiology of Kruppel-like Factors in Colorectal Cancer.
Ghaleb AM, Yang VW.
Curr Colorectal Cancer Rep. 2008 Apr;4(2):59-64. (REVIEW)
PMID 18504508
 
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Contributor(s)

Written10-2008Amr M Ghaleb, Vincent W Yang
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine Atlanta, Georgia, USA

Citation

This paper should be referenced as such :
Ghaleb, AM ; Yang, VW
KLF4 (Kruppel-like factor 4 (gut))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):639-643.
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