KLF6 (Krüppel like factor 6)

2007-03-01   Scott 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

Identity

HGNC
LOCATION
10p15.1
LOCUSID
ALIAS
BCD1,CBA1,COPEB,CPBP,GBF,PAC1,ST12,ZF9
FUSION GENES

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.

Proteins

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.

Implicated in

Bibliography

Pubmed IDLast YearTitleAuthors
151729982004Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1.Benzeno S et al
114292962001Co-localization of KLF6 and KLF4 with pregnancy-specific glycoproteins during human placenta development.Blanchon L et al
124336972002Transcriptional 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 et al
126516262003Deletion, mutation, and loss of expression of KLF6 in human prostate cancer.Chen C et al
124071522002Regulation of corneal keratin-12 gene expression by the human Krüppel-like transcription factor 6.Chiambaretta F et al
158247332005Genetic alterations of the KLF6 gene in gastric cancer.Cho YG et al
145277172003Identification of the Drosophila progenitor of mammalian Krüppel-like factors 6 and 7 and a determinant of fly development.De Graeve F et al
167781002006Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination.DiFeo A et al
112742342001Klf6 is a zinc finger protein expressed in a cell-specific manner during kidney development.Fischer EA et al
160547102005Genomic organization and functional analysis of the gene encoding the Krüppel-like transcription factor KLF6.Gehrau RC et al
151729912004Krüppel-like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells.Ito G et al
127409102003KLF6, a putative tumor suppressor gene, is mutated in astrocytic gliomas.Jeng YM et al
98379631998Transcriptional 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 et al
150647202004Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6.Kimmelman AC et al
106662042000Transcriptional activation of urokinase by the Krüppel-like factor Zf9/COPEB activates latent TGF-beta1 in vascular endothelial cells.Kojima S et al
154869212004Frequent inactivation of the tumor suppressor Kruppel-like factor 6 (KLF6) in hepatocellular carcinoma.Kremer-Tal S et al
114728502001Embryonic expression of Krüppel-like factor 6 in neural and non-neural tissues.Laub F et al
159172482005Krüppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1.Li D et al
162343532006Developmental regulation of yolk sac hematopoiesis by Kruppel-like factor 6.Matsumoto N et al
155574392004Developmentally regulated expression of KLF6 in the mouse cornea and lens.Nakamura H et al
159949512005Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread.Narla G et al
157350052005A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk.Narla G et al
117525792001KLF6, a candidate tumor suppressor gene mutated in prostate cancer.Narla G et al
108020672000The Krüppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact.Okano J et al
96891091998Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis.Ratziu V et al
150577482004Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer.Reeves HL et al
151310182004Transcriptional 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 et al
153780032004A new role for the Kruppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function.Slavin DA et al
172232582007Genome-wide single nucleotide polymorphism analysis of lung cancer risk detects the KLF6 gene.Spinola M et al
125901402003Transcriptional activation of the human inducible nitric-oxide synthase promoter by Kruppel-like factor 6.Warke VG et al
122351612002The Kruppel-like factor Zf9 and proteins in the Sp1 family regulate the expression of HSP47, a collagen-specific molecular chaperone.Yasuda K et al
171435132007KLF6: mutational analysis and effect on cancer cell proliferation.Yin D et al
107227372000Cell-specific transcription of leukotriene C(4) synthase involves a Kruppel-like transcription factor and Sp1.Zhao JL et al

Other Information

Locus ID:

NCBI: 1316
MIM: 602053
HGNC: 2235
Ensembl: ENSG00000067082

Variants:

dbSNP: 1316
ClinVar: 1316
TCGA: ENSG00000067082
COSMIC: KLF6

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000067082ENST00000469435Q99612
ENSG00000067082ENST00000497571Q99612
ENSG00000067082ENST00000542957Q99612

Expression (GTEx)

0
50
100
150
200
250
300

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
150673242004Gene expression profiling predicts clinical outcome of prostate cancer.171
150673242004Gene expression profiling predicts clinical outcome of prostate cancer.171
117525792001KLF6, a candidate tumor suppressor gene mutated in prostate cancer.139
157350052005A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk.88
163854512006A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.69
159172482005Krüppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1.57
150577482004Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer.56
210568922011HIV-1 infects macrophages by exploiting an endocytic route dependent on dynamin, Rac1 and Pak1.54
167781002006Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination.49
154869212004Frequent inactivation of the tumor suppressor Kruppel-like factor 6 (KLF6) in hepatocellular carcinoma.48

Citation

Scott L. Friedman ; Goutham Narla ; John A. Martignetti

KLF6 (Krüppel like factor 6)

Atlas Genet Cytogenet Oncol Haematol. 2007-03-01

Online version: http://atlasgeneticsoncology.org/gene/44002/klf6