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KLF6 (Krüppel like factor 6)

Identity

Other namesBCD1
COPEB (Core promoter binding protein)
CPBP
GBF
PAC1
ST12
Zf9
HGNC (Hugo) KLF6
Location 10p15.1
Location_base_pair Starts at 3811239 and ends at 3817455 bp from pter ( according to hg18-Mar_2006)  [Mapping]

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.

External links

Nomenclature
HGNC (Hugo)KLF6   2235
Entrez_Gene (NCBI)KLF6  1316  Kruppel-like factor 6
Cards
AtlasKLF6ID44002ch10p15
GeneCards (Weizmann)KLF6
Ensembl (Hinxton)ENSG00000067082 [Gene_View]  KLF6 [Vega]
AceView (NCBI)KLF6
Genatlas (Paris)KLF6
euGene (Indiana)1316
SOURCE (Stanford)NM_001160124 NM_001160125 NM_001300
Gene Expression (Array Express) ENSG00000067082
Genomic and cartography
GoldenPath (UCSC)KLF6  -  10p15.1   chr10:3811239-3817455 -  10p15   [Description]    (hg18-Mar_2006)
EnsemblKLF6 - 10p15 [CytoView]
Mapping of homologs : NCBIKLF6 [Mapview]
OMIM137215   176807   602053   
Gene and transcription
Gene : Genbank (Entrez)AB017493 AF001461 AI355637 AK293259 AK316596
Reference sequence (RefSeq transcript) :SRSNM_001160124 NM_001160125 NM_001300
Reference transcript : EntrezNM_001160124 NM_001160125 NM_001300
RefSeq genomic : SRSAC_000053 AC_000142 NC_000010 NG_012277 NT_008705 NW_001837930 NW_924584
RefSeq genomic : EntrezAC_000053 AC_000142 NC_000010 NG_012277 NT_008705 NW_001837930 NW_924584
Consensus coding sequences : CCDS NCBIKLF6
Cluster EST : UnigeneHs.720439 [ SRS ] Hs.720439 [ NCBI ]
Alternative Splicing : Fast-db (Paris)422
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtQ99612 (SRS) Q99612 (Expasy) Q99612 (Uniprot)
With graphics : InterProQ99612
Splice isoforms : VarSplice FASTAQ99612(VarSplice FASTA)
Domaine pattern : Prosite (SRS)ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domain pattern : Prosite (Expaxy)ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (SRS)Znf_C2H2    Znf_C2H2-like    Znf_C2H2/integrase_DNA-bd   
Domains : Interpro (EBI)Znf_C2H2    Znf_C2H2-like    Znf_C2H2/integrase_DNA-bd   
Related proteins : CluSTrQ99612
Domain families : Pfam SRSzf-C2H2 (PF00096)   
Domain families : Pfam Sangerzf-C2H2 (PF00096)   
Domain families : Pfam NCBIpfam00096   
Domain families : Smart EMBLZnF_C2H2 (SM00355)  
Blocks (Seattle)Q99612
Crystal structure of protein : PDB SRS
Crystal structure of protein : PDBSum
Crystal structure of protein : IMB
Crystal structure of protein : PDB RSDB
HPRD03632
Protein Interaction databases
DIP (DOE-UCLA)Q99612
IntAct (EBI)Q99612
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBIKLF6
SNP : GeneSNP UtahKLF6
SNP : HGBaseKLF6
Genetic variants : HAPMAPKLF6
Somatic Mutations in Cancer : COSMICKLF6 
Mutations and Diseases : HGMDKLF6
Hereditary diseases : OMIM137215    176807    602053   
Hereditary diseases : GENETests137215    176807    602053   
Diseases : Genetic AssociationKLF6
General knowledge
Homologs : HomoloGeneKLF6
Homology/Alignments : Family Browser UCSCKLF6
Phylogenetic Trees/Animal Genes : TreeFamKLF6
Chemical/Protein Interactions : CTD1316
Keywords Ontology : AmiGOdouble-stranded DNA binding  transcription factor activity  intracellular  nucleus  cytoplasm  regulation of transcription, DNA-dependent  zinc ion binding  transcription activator activity  cytokine-mediated signaling pathway  B cell differentiation  wound healing  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  
Keywords Ontology : EGO-EBIdouble-stranded DNA binding  transcription factor activity  intracellular  nucleus  cytoplasm  regulation of transcription, DNA-dependent  zinc ion binding  transcription activator activity  cytokine-mediated signaling pathway  B cell differentiation  wound healing  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  
Pathways : BIOCARTA
Pathways : KEGG
Other databases
Probes
Probes : ImagenesKLF6 Related clones (RZPD - Berlin)
Literature
PubMed77 Pubmed reference(s) in Entrez
PubGeneKLF6

Bibliography

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
 
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
 
Transcriptional activation of urokinase by the Krˆºppel-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
 
The Krˆºppel-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
 
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
 
Co-localization of KLF6 and KLF4 with pregnancy-specific glycoproteins during human placenta development.
Blanchon L, Bocco JL, Gallot D, Gachon AM, Lˆ©mery D, Dˆ©chelotte P, Dastugue B, Sapin V
Mechanisms of development. 2001 ; 105 (1-2) : 185-189.
PMID 11429296
 
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
 
Embryonic expression of Krˆºppel-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
 
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
 
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, Sˆ°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, Bernabˆ©u C
Blood. 2002 ; 100 (12) : 4001-4010.
PMID 12433697
 
Regulation of corneal keratin-12 gene expression by the human Krˆºppel-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
 
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
 
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
 
Identification of the Drosophila progenitor of mammalian Krˆºppel-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
 
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 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
 
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
 
Krˆºppel-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
 
Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6.
Kimmelman AC, Qiao RF, Narla G, Banno A, Lau N, Bos PD, Nuˆ±ez Rodriguez N, Liang BC, Guha A, Martignetti JA, Friedman SL, Chan AM
Oncogene. 2004 ; 23 (29) : 5077-5083.
PMID 15064720
 
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
 
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
 
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, Lˆ„pez-Dˆ‚az FJ, Chatton B, Bocco JL
Oncogene. 2004 ; 23 (50) : 8196-8205.
PMID 15378003
 
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
 
Genomic organization and functional analysis of the gene encoding the Krˆºppel-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
 
Regulation of Kruppel-like factor 6 tumor suppressor activity by acetylation.
Li D, Yea S, Dolios G, Martignetti JA, Narla G, Wang R, Walsh MJ, Friedman SL
Cancer research. 2005 ; 65 (20) : 9216-9225.
PMID 16230382
 
Krˆºppel-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
 
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
 
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
 
E-cadherin is a novel transcriptional target of the KLF6 tumor suppressor.
DiFeo A, Narla G, Camacho-Vanegas O, Nishio H, Rose SL, Buller RE, Friedman SL, Walsh MJ, Martignetti JA
Oncogene. 2006 ; 25 (44) : 6026-6031.
PMID 16702959
 
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
 
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
 
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
 
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
 
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Contributor(s)

Written03-2007Scott L. Friedman, Goutham Narla, John A. Martignetti

Citation

This paper should be referenced as such :
Friedman SL, Narla G, Martignetti JA . KLF6 (Krüppel like factor 6). Atlas Genet Cytogenet Oncol Haematol. March 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/KLF6ID44002ch10p15.html

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