KLF6 (Krüppel like factor 6)

Identity

Other names	BCD1
	COPEB (Core promoter binding protein)
	CPBP
	GBF
	PAC1
	ST12
	Zf9
Hugo	KLF6
Location	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.

External links

	Nomenclature
Hugo	KLF6
GDB	KLF6
Entrez_Gene	KLF6  1316  Kruppel-like factor 6
	Cards
Atlas	KLF6ID44002ch10p15
GeneCards	KLF6
Ensembl	KLF6 [Search_View]   ENSG00000067082 [Gene_View]
Genatlas	KLF6
GeneLynx	KLF6
eGenome	KLF6
euGene	1316
	Genomic and cartography
GoldenPath	KLF6  -  10p15.1   chr10:3811241-3817455 -  10p15   [Description]    (hg18-Mar_2006)
Ensembl	KLF6 - 10p15 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	KLF6
	Gene and transcription
Genbank	AB017493 [ ENTREZ ]
Genbank	AF001461 [ ENTREZ ]
Genbank	AI355637 [ ENTREZ ]
Genbank	BC000311 [ ENTREZ ]
Genbank	BC004301 [ ENTREZ ]
RefSeq	NM_001008490 [ SRS ]    NM_001008490 [ ENTREZ ]
RefSeq	NM_001300 [ SRS ]    NM_001300 [ ENTREZ ]
RefSeq	AC_000053 [ SRS ]    AC_000053 [ ENTREZ ]
RefSeq	NC_000010 [ SRS ]    NC_000010 [ ENTREZ ]
RefSeq	NT_077567 [ SRS ]    NT_077567 [ ENTREZ ]
RefSeq	NW_924584 [ SRS ]    NW_924584 [ ENTREZ ]
AceView	KLF6 AceView - NCBI
Unigene	Hs.4055 [ SRS ]    Hs.4055 [ NCBI ]     HS4055 [ spliceNest ]
Fast-db	422 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q99612 [ SRS]    Q99612 [ EXPASY ]     Q99612 [ INTERPRO ]
Prosite	PS00028 ZINC_FINGER_C2H2_1 [ SRS ]    PS00028 ZINC_FINGER_C2H2_1 [ Expasy ]
Prosite	PS50157 ZINC_FINGER_C2H2_2 [ SRS ]    PS50157 ZINC_FINGER_C2H2_2 [ Expasy ]
Interpro	IPR007087 Znf_C2H2 [ SRS ]    IPR007087 Znf_C2H2 [ EBI ]
Interpro	IPR015880 Znf_C2H2-like [ SRS ]    IPR015880 Znf_C2H2-like [ EBI ]
Interpro	IPR013087 Znf_C2H2/integrase_DNA-bd [ SRS ]    IPR013087 Znf_C2H2/integrase_DNA-bd [ EBI ]
CluSTr	Q99612
Pfam	PF00096 zf-C2H2 [ SRS ]    PF00096 zf-C2H2 [ Sanger ]    pfam00096 [ NCBI-CDD ]
Smart	SM00355 ZnF_C2H2 [EMBL]
Prodom	PD000003 Znf_C2H2[INRA-Toulouse]
Prodom	Q99612 KLF6_HUMAN [ Domain structure ]   Q99612 KLF6_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	Q99612
HPRD	03632
	Protein Interaction databases
DIP	Q99612
IntAct	Q99612
	Polymorphism : SNP, mutations, diseases
OMIM	137215;176807;602053    [ map ]
GENECLINICS	137215;176807;602053
SNP	KLF6 [dbSNP-NCBI]
SNP	NM_001008490 [SNP-NCI]
SNP	NM_001300 [SNP-NCI]
SNP	KLF6 [GeneSNPs - Utah]  KLF6] [HGBASE - SRS]
HAPMAP	KLF6 [HAPMAP]
HGMD	KLF6
	General knowledge
Family Browser	KLF6 [UCSC Family Browser]
SOURCE	NM_001008490
SOURCE	NM_001300
SMD	Hs.4055
SAGE	Hs.4055
GO	molecular_function [Amigo]  molecular_function
GO	nucleic acid binding [Amigo]  nucleic acid binding
GO	DNA binding [Amigo]  DNA binding
GO	cellular_component [Amigo]  cellular_component
GO	intracellular [Amigo]  intracellular
GO	nucleus [Amigo]  nucleus
GO	transcription [Amigo]  transcription
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
GO	biological_process [Amigo]  biological_process
GO	zinc ion binding [Amigo]  zinc ion binding
GO	cell growth [Amigo]  cell growth
GO	transcription activator activity [Amigo]  transcription activator activity
GO	B cell differentiation [Amigo]  B cell differentiation
GO	metal ion binding [Amigo]  metal ion binding
PubGene	KLF6
TreeFam	KLF6
CTD	1316 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	KLF6 Related clones (RZPD - Berlin)
	PubMed
PubMed	49 Pubmed reference(s) in LocusLink

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.

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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)

Written	03-2007	Scott 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:24:32 2008