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KLF6 (Krüppel like factor 6)

Written2007-03Scott L. Friedman, Goutham Narla, John A. Martignetti
Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave., Room 11-70C, New York, NY 10029-6574, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesBCD1
ST12
COPEB
core promoter element binding protein
Alias_symbol (synonym)CPBP
GBF
Zf9
PAC1
Other aliasCOPEB (Core promoter binding protein)
HGNC (Hugo) KLF6
LocusID (NCBI) 1316
Atlas_Id 44002
Location 10p15.1  [Link to chromosome band 10p15]
Location_base_pair Starts at 3775996 and ends at 3785281 bp from pter ( according to hg19-Feb_2009)  [Mapping KLF6.png]
Fusion genes
(updated 2016)		CBWD6 (9q21.11) / KLF6 (10p15.1)KLF6 (10p15.1) / KLF6 (10p15.1)KLF6 (10p15.1) / SHPRH (6q24.3)
LMAN1 (18q21.32) / KLF6 (10p15.1)SON (21q22.11) / KLF6 (10p15.1)ZFPM1 (16q24.2) / KLF6 (10p15.1)

DNA/RNA

Description Spans 11 kb; five exons; 4 CDS exons.
Transcription Full length transcript of 4.1 kb, open reading frame 849 bp. There are at least three alternative splice transcripts.

Protein

Description Full length transcript encodes a 283 amino acids protein, 42 kDa, with a 201 amino acids transactivation domain and an 82 amino acids DNA binding domain with 3 C2H2 zinc fingers. There is at least one putative nuclear localization signal immediately 5' to the DNA binding domain.
There are at least three alternative splice transcripts encoding proteins of 195 (KLF6-SV1), 237 (KLF6-SV3), and 241 amino acids (KLF6-SV2).
Several post-translational modifications including phosphorylation, ubiquitinylation, acetylation are suggested based on encoded protein sequence motifs.
Expression Ubiquitously expressed in adult tissues, restricted during embryogenesis but includes placenta, neural and non-neural tissues, and cornea. Full-length KLF6 downregulated in many human cancers (see below). Expression pattern of KLF6 splice variants may be upregulated.
Localisation Found in both nucleus and cytoplasm, but predominantly nuclear. Splice variants SV1 and SV2 primarily cytoplasmic and believed to be the result of loss of nuclear localization signal (NLS). Splice variant 3 retains the NLS.
Function Tumor suppressor gene, immediate early gene in tissue injury and fibrosis, during adenoviral and pseudomonas infections and during ischemic reperfusion in kidney.
Transactivator of multiple target genes including p21, TGFbeta1, TGFbeta receptors type II and TGFbeta receptors type III, human keratin 4 and 12 genes: inducible nitric oxide synthase, endoglin, insulin-like growth factor receptor 1, multi-drug resistance transporters, E-cadherin, leukotriene C(4)(LTC4S), laminin 111, acid ceramidase, alpha 1 proteinase inhibitor.
Suppresses growth by inducing p21, sequestering cyclin D1 and/or inhibiting c-jun oncogene.
Promotes differentiation of preadipocytes to adipocytes in culture and hepatocytes in vivo.
Contributes to fetal development of mouse cornea and lens; and immune and hematopoietic systems by contributing to hemangioblast phenotype.
Interacts with the core promoter element of a TATA box-less gene.
Induces apoptosis of lung cancer cells.
Homology The 47 N-terminal amino acids are identical to KLF7, and the 82 amino acids DNA binding domain highly homologous to other members of the KLF family. Also homologous to the Drosophila Luna gene.

Mutations

Germinal None identified to date. However, a germline single nucleotide intronic polymorphism (IVS1-27 G > A) has been identified that creates a novel SRp40 DNA binding site, therby increasing the generation of three alternatively spliced mRNAs, and which is associated with an increased risk of prostate cancer. Other low frequency coding and non-coding SNPs have been identified.
Somatic A number of somatic mutations were originally identified in prostate cancer and shown to result in loss of function. These include Trp64Arg, Ser116Pro, Ala123Asp and Ser137X.

Bibliography

Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1.
Benzeno S, Narla G, Allina J, Cheng GZ, Reeves HL, Banck MS, Odin JA, Diehl JA, Germain D, Friedman SL
Cancer research. 2004 ; 64 (11) : 3885-3891.
PMID 15172998
 
Co-localization of KLF6 and KLF4 with pregnancy-specific glycoproteins during human placenta development.
Blanchon L, Bocco JL, Gallot D, Gachon AM, Lémery D, Déchelotte P, Dastugue B, Sapin V
Mechanisms of development. 2001 ; 105 (1-2) : 185-189.
PMID 11429296
 
Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury.
Botella LM, S´nchez-Elsner T, Sanz-Rodriguez F, Kojima S, Shimada J, Guerrero-Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP, Ramirez JR, Friedman S, Bernabéu C
Blood. 2002 ; 100 (12) : 4001-4010.
PMID 12433697
 
Deletion, mutation, and loss of expression of KLF6 in human prostate cancer.
Chen C, Hyytinen ER, Sun X, Helin HJ, Koivisto PA, Frierson HF Jr, Vessella RL, Dong JT
The American journal of pathology. 2003 ; 162 (4) : 1349-1354.
PMID 12651626
 
Regulation of corneal keratin-12 gene expression by the human Krüppel-like transcription factor 6.
Chiambaretta F, Blanchon L, Rabier B, Kao WW, Liu JJ, Dastugue B, Rigal D, Sapin V
Investigative ophthalmology & visual science. 2002 ; 43 (11) : 3422-3429.
PMID 12407152
 
Genetic alterations of the KLF6 gene in gastric cancer.
Cho YG, Kim CJ, Park CH, Yang YM, Kim SY, Nam SW, Lee SH, Yoo NJ, Lee JY, Park WS
Oncogene. 2005 ; 24 (28) : 4588-4590.
PMID 15824733
 
Identification of the Drosophila progenitor of mammalian Krüppel-like factors 6 and 7 and a determinant of fly development.
De Graeve F, Smaldone S, Laub F, Mlodzik M, Bhat M, Ramirez F
Gene. 2003 ; 314 : 55-62.
PMID 14527717
 
Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination.
DiFeo A, Narla G, Hirshfeld J, Camacho-Vanegas O, Narla J, Rose SL, Kalir T, Yao S, Levine A, Birrer MJ, Bonome T, Friedman SL, Buller RE, Martignetti JA
Clinical cancer research : an official journal of the American Association for Cancer Research. 2006 ; 12 (12) : 3730-3739.
PMID 16778100
 
Klf6 is a zinc finger protein expressed in a cell-specific manner during kidney development.
Fischer EA, Verpont MC, Garrett-Sinha LA, Ronco PM, Rossert JA
Journal of the American Society of Nephrology : JASN. 2001 ; 12 (4) : 726-735.
PMID 11274234
 
Genomic organization and functional analysis of the gene encoding the Krüppel-like transcription factor KLF6.
Gehrau RC, D'Astolfo DS, Prieto C, Bocco JL, Koritschoner NP
Biochimica et biophysica acta. 2005 ; 1730 (2) : 137-146.
PMID 16054710
 
Krüppel-like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells.
Ito G, Uchiyama M, Kondo M, Mori S, Usami N, Maeda O, Kawabe T, Hasegawa Y, Shimokata K, Sekido Y
Cancer research. 2004 ; 64 (11) : 3838-3843.
PMID 15172991
 
KLF6, a putative tumor suppressor gene, is mutated in astrocytic gliomas.
Jeng YM, Hsu HC
International journal of cancer. Journal international du cancer. 2003 ; 105 (5) : 625-629.
PMID 12740910
 
Transcriptional activation of transforming growth factor beta1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1. Potential mechanisms for autocrine fibrogenesis in response to injury.
Kim Y, Ratziu V, Choi SG, Lalazar A, Theiss G, Dang Q, Kim SJ, Friedman SL
The Journal of biological chemistry. 1998 ; 273 (50) : 33750-33758.
PMID 9837963
 
Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6.
Kimmelman AC, Qiao RF, Narla G, Banno A, Lau N, Bos PD, Nuñez Rodriguez N, Liang BC, Guha A, Martignetti JA, Friedman SL, Chan AM
Oncogene. 2004 ; 23 (29) : 5077-5083.
PMID 15064720
 
Transcriptional activation of urokinase by the Krüppel-like factor Zf9/COPEB activates latent TGF-beta1 in vascular endothelial cells.
Kojima S, Hayashi S, Shimokado K, Suzuki Y, Shimada J, Crippa MP, Friedman SL
Blood. 2000 ; 95 (4) : 1309-1316.
PMID 10666204
 
Frequent inactivation of the tumor suppressor Kruppel-like factor 6 (KLF6) in hepatocellular carcinoma.
Kremer-Tal S, Reeves HL, Narla G, Thung SN, Schwartz M, Difeo A, Katz A, Bruix J, Bioulac-Sage P, Martignetti JA, Friedman SL
Hepatology (Baltimore, Md.). 2004 ; 40 (5) : 1047-1052.
PMID 15486921
 
Embryonic expression of Krüppel-like factor 6 in neural and non-neural tissues.
Laub F, Aldabe R, Ramirez F, Friedman S
Mechanisms of development. 2001 ; 106 (1-2) : 167-170.
PMID 11472850
 
Krüppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1.
Li D, Yea S, Li S, Chen Z, Narla G, Banck M, Laborda J, Tan S, Friedman JM, Friedman SL, Walsh MJ
The Journal of biological chemistry. 2005 ; 280 (29) : 26941-26952.
PMID 15917248
 
Developmental regulation of yolk sac hematopoiesis by Kruppel-like factor 6.
Matsumoto N, Kubo A, Liu H, Akita K, Laub F, Ramirez F, Keller G, Friedman SL
Blood. 2006 ; 107 (4) : 1357-1365.
PMID 16234353
 
Developmentally regulated expression of KLF6 in the mouse cornea and lens.
Nakamura H, Chiambaretta F, Sugar J, Sapin V, Yue BY
Investigative ophthalmology & visual science. 2004 ; 45 (12) : 4327-4332.
PMID 15557439
 
Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread.
Narla G, DiFeo A, Yao S, Banno A, Hod E, Reeves HL, Qiao RF, Camacho-Vanegas O, Levine A, Kirschenbaum A, Chan AM, Friedman SL, Martignetti JA
Cancer research. 2005 ; 65 (13) : 5761-5768.
PMID 15994951
 
A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk.
Narla G, Difeo A, Reeves HL, Schaid DJ, Hirshfeld J, Hod E, Katz A, Isaacs WB, Hebbring S, Komiya A, McDonnell SK, Wiley KE, Jacobsen SJ, Isaacs SD, Walsh PC, Zheng SL, Chang BL, Friedrichsen DM, Stanford JL, Ostrander EA, Chinnaiyan AM, Rubin MA, Xu J, Thibodeau SN, Friedman SL, Martignetti JA
Cancer research. 2005 ; 65 (4) : 1213-1222.
PMID 15735005
 
KLF6, a candidate tumor suppressor gene mutated in prostate cancer.
Narla G, Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Glucksman MJ, Narla J, Eng FJ, Chan AM, Ferrari AC, Martignetti JA, Friedman SL
Science (New York, N.Y.). 2001 ; 294 (5551) : 2563-2566.
PMID 11752579
 
The Krüppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact.
Okano J, Opitz OG, Nakagawa H, Jenkins TD, Friedman SL, Rustgi AK
FEBS letters. 2000 ; 473 (1) : 95-100.
PMID 10802067
 
Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis.
Ratziu V, Lalazar A, Wong L, Dang Q, Collins C, Shaulian E, Jensen S, Friedman SL
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (16) : 9500-9505.
PMID 9689109
 
Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer.
Reeves HL, Narla G, Ogunbiyi O, Haq AI, Katz A, Benzeno S, Hod E, Harpaz N, Goldberg S, Tal-Kremer S, Eng FJ, Arthur MJ, Martignetti JA, Friedman SL
Gastroenterology. 2004 ; 126 (4) : 1090-1103.
PMID 15057748
 
Transcriptional activation of the insulin-like growth factor I receptor gene by the Kruppel-like factor 6 (KLF6) tumor suppressor protein: potential interactions between KLF6 and p53.
Rubinstein M, Idelman G, Plymate SR, Narla G, Friedman SL, Werner H
Endocrinology. 2004 ; 145 (8) : 3769-3777.
PMID 15131018
 
A new role for the Kruppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function.
Slavin DA, Koritschoner NP, Prieto CC, López-Dí FJ, Chatton B, Bocco JL
Oncogene. 2004 ; 23 (50) : 8196-8205.
PMID 15378003
 
Genome-wide single nucleotide polymorphism analysis of lung cancer risk detects the KLF6 gene.
Spinola M, Leoni VP, Galvan A, Korsching E, Conti B, Pastorino U, Ravagnani F, Columbano A, Skaug V, Haugen A, Dragani TA
Cancer letters. 2007 ; 251 (2) : 311-316.
PMID 17223258
 
Transcriptional activation of the human inducible nitric-oxide synthase promoter by Kruppel-like factor 6.
Warke VG, Nambiar MP, Krishnan S, Tenbrock K, Geller DA, Koritschoner NP, Atkins JL, Farber DL, Tsokos GC
The Journal of biological chemistry. 2003 ; 278 (17) : 14812-14819.
PMID 12590140
 
The Kruppel-like factor Zf9 and proteins in the Sp1 family regulate the expression of HSP47, a collagen-specific molecular chaperone.
Yasuda K, Hirayoshi K, Hirata H, Kubota H, Hosokawa N, Nagata K
The Journal of biological chemistry. 2002 ; 277 (47) : 44613-44622.
PMID 12235161
 
KLF6: mutational analysis and effect on cancer cell proliferation.
Yin D, Komatsu N, Miller CW, Chumakov AM, Marschesky A, McKenna R, Black KL, Koeffler HP
International journal of oncology. 2007 ; 30 (1) : 65-72.
PMID 17143513
 
Cell-specific transcription of leukotriene C(4) synthase involves a Kruppel-like transcription factor and Sp1.
Zhao JL, Austen KF, Lam BK
The Journal of biological chemistry. 2000 ; 275 (12) : 8903-8910.
PMID 10722737
 

Citation

This paper should be referenced as such :
Martignetti, JA ; Narla, G ; Friedman, SL
KLF6 (Kruppel like factor 6)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):229-231.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/KLF6ID44002ch10p15.html

External links

Nomenclature
HGNC (Hugo)KLF6   2235
Cards
AtlasKLF6ID44002ch10p15
Entrez_Gene (NCBI)KLF6  1316  Kruppel like factor 6
AliasesBCD1; CBA1; COPEB; CPBP; 
GBF; PAC1; ST12; ZF9
GeneCards (Weizmann)KLF6
Ensembl hg19 (Hinxton)ENSG00000067082 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000067082 [Gene_View]  chr10:3775996-3785281 [Contig_View]  KLF6 [Vega]
ICGC DataPortalENSG00000067082
TCGA cBioPortalKLF6
AceView (NCBI)KLF6
Genatlas (Paris)KLF6
WikiGenes1316
SOURCE (Princeton)KLF6
Genetics Home Reference (NIH)KLF6
Genomic and cartography
GoldenPath hg38 (UCSC)KLF6  -     chr10:3775996-3785281 -  10p15.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KLF6  -     10p15.2   [Description]    (hg19-Feb_2009)
EnsemblKLF6 - 10p15.2 [CytoView hg19]  KLF6 - 10p15.2 [CytoView hg38]
Mapping of homologs : NCBIKLF6 [Mapview hg19]  KLF6 [Mapview hg38]
OMIM176807   602053   613659   
Gene and transcription
Genbank (Entrez)AB017493 AF001461 AI355637 AK293259 AK316596
RefSeq transcript (Entrez)NM_001008490 NM_001160124 NM_001160125 NM_001300
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KLF6
Cluster EST : UnigeneHs.709396 [ NCBI ]
CGAP (NCI)Hs.709396
Alternative Splicing GalleryENSG00000067082
Gene ExpressionKLF6 [ NCBI-GEO ]   KLF6 [ EBI - ARRAY_EXPRESS ]   KLF6 [ SEEK ]   KLF6 [ MEM ]
Gene Expression Viewer (FireBrowse)KLF6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1316
GTEX Portal (Tissue expression)KLF6
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ99612   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ99612  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ99612
Splice isoforms : SwissVarQ99612
PhosPhoSitePlusQ99612
Domaine pattern : Prosite (Expaxy)ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (EBI)Znf_C2H2    Znf_C2H2-like    Znf_C2H2/integrase_DNA-bd   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Domain families : Smart (EMBL)ZnF_C2H2 (SM00355)  
Conserved Domain (NCBI)KLF6
DMDM Disease mutations1316
Blocks (Seattle)KLF6
SuperfamilyQ99612
Human Protein AtlasENSG00000067082
Peptide AtlasQ99612
HPRD03632
IPIIPI00293523   IPI00478435   IPI00014502   IPI00014503   IPI00930147   
Protein Interaction databases
DIP (DOE-UCLA)Q99612
IntAct (EBI)Q99612
FunCoupENSG00000067082
BioGRIDKLF6
STRING (EMBL)KLF6
ZODIACKLF6
Ontologies - Pathways
QuickGOQ99612
Ontology : AmiGORNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  fibrillar center  protein binding  nucleus  nucleus  nucleolus  cytosol  transcription from RNA polymerase II promoter  B cell differentiation  intracellular membrane-bounded organelle  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  
Ontology : EGO-EBIRNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  fibrillar center  protein binding  nucleus  nucleus  nucleolus  cytosol  transcription from RNA polymerase II promoter  B cell differentiation  intracellular membrane-bounded organelle  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  
NDEx NetworkKLF6
Atlas of Cancer Signalling NetworkKLF6
Wikipedia pathwaysKLF6
Orthology - Evolution
OrthoDB1316
GeneTree (enSembl)ENSG00000067082
Phylogenetic Trees/Animal Genes : TreeFamKLF6
HOVERGENQ99612
HOGENOMQ99612
Homologs : HomoloGeneKLF6
Homology/Alignments : Family Browser (UCSC)KLF6
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLF6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLF6
dbVarKLF6
ClinVarKLF6
1000_GenomesKLF6 
Exome Variant ServerKLF6
ExAC (Exome Aggregation Consortium)KLF6 (select the gene name)
Genetic variants : HAPMAP1316
Genomic Variants (DGV)KLF6 [DGVbeta]
DECIPHERKLF6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKLF6 
Mutations
ICGC Data PortalKLF6 
TCGA Data PortalKLF6 
Broad Tumor PortalKLF6
OASIS PortalKLF6 [ Somatic mutations - Copy number]
Cancer Gene: CensusKLF6 
Somatic Mutations in Cancer : COSMICKLF6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDKLF6
intOGen PortalKLF6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch KLF6
DgiDB (Drug Gene Interaction Database)KLF6
DoCM (Curated mutations)KLF6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KLF6 (select a term)
intoGenKLF6
NCG5 (London)KLF6
Cancer3DKLF6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM176807    602053    613659   
Orphanet
MedgenKLF6
Genetic Testing Registry KLF6
NextProtQ99612 [Medical]
TSGene1316
GENETestsKLF6
Target ValidationKLF6
Huge Navigator KLF6 [HugePedia]
snp3D : Map Gene to Disease1316
BioCentury BCIQKLF6
ClinGenKLF6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1316
Chemical/Pharm GKB GenePA26751
Clinical trialKLF6
Miscellaneous
canSAR (ICR)KLF6 (select the gene name)
Probes
Litterature
PubMed141 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKLF6
EVEXKLF6
GoPubMedKLF6
iHOPKLF6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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