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KLF5 : Kruppel-like factor 5 (intestinal)

Written2006-10Ceshi Chen, Yinfa Zhou, Jin-Tang Dong
The Center for Cell Biology, Cancer Research Albany Medical College MS355/350, Mail code 165, 47 New Scotland Ave. Albany, NY 12208, USA

(Note : for Links provided by Atlas : click)

Identity

Other namesIKLF
BTEB2
HGNC (Hugo) KLF5
LocusID (NCBI) 688
Atlas_Id 41074
Location 13q22.1  [Link to chromosome band 13q22]
Location_base_pair Starts at 73629114 and ends at 73651680 bp from pter ( according to hg19-Feb_2009)  [Mapping KLF5.png]
 
Fusion genes
(updated 2016)
FBXL3 (13q22.3) / KLF5 (13q22.1)KLF5 (13q22.1) / TMC4 (19q13.42)RAP1GDS1 (4q23) / KLF5 (13q22.1)
Note FISH study in PC-3 prostate cancer cell line using BAC 505F3 as a probe

DNA/RNA

 
  Black box: Exon
Description KLF5 gene encompasses 4 exons which span about 18.7 kb of DNA. BAC clone RPCI-505F3 contains the complete KLF5 genome sequence.
Transcription about 3.4 Kb mRNA, 1374 bp open reading frame

Protein

 
  TAD: transactivation domain, PY: PPPSY sequence
Description 457 amino acids; about 55 kDa protein; KLF5 protein undergoes numerous post translational modifications: phosphorylation, acetylation, and ubiquitination. The major transactivation domain is proline rich and contains a PY motif (324-328), which can bind to E3 ubiquitin ligase WWP1. Three zinc finger domains at C-terminus can bind to GC rich DNA sequence.
Expression widely expressed in intestine, prostate, breast, lung, bladder, pancreas, placenta, uterus, skin, and skeletal muscle.
Localisation nucleus
Function KLF5 is a transcription factor. Many KLF5 target genes, such as PDGFa, PPARg, NFkB, cyclinD1, KLF4, and TCR, have been identified in different cell models. KLF5 regulates cell proliferation, cell cycle, apoptosis, and differentiation. KLF5 is an important transcription factor for cardiovascular remodeling and tumor angiogenesis. KLF5 is essential for mouse embryo development. Additionally, KLF5 may play an important role in several tumor types including breast, prostate, bladder, colon, esophagus, and skin.
Homology KLF5 gene is highly-conserved among species (from human to Drosophila). KLF5 belongs to the SP1/KLF transcription factor family

Mutations

Somatic The KLF5 gene is rarely mutated in human prostate cancer. One point mutation (A --> G), which change Met294 to Val, has been found in the breast cancer cell line MDA-MB-231.

Implicated in

Note
Entity Breast cancer
Disease The KLF5 gene is deleted in about 43% breast cancer cell lines. Consistently, KLF5 mRNA is down-regulated in these cell lines. In 9 breast cancer cell lines without KLF5 mRNA loss, KLF5 protein is excessively degraded through ubiquitin-proteasome pathway. Forced expression of KLF5 inhibits T-47D cancer cell growth in vitro. In contrast, KLF5 expression is upregulated in clinical breast tumor samples (see below)
Prognosis Recently, high level of KLF5 mRNA expression is found to be associated with shorter survival for breast cancer patients. Using tissue microarray, we performed immunohistochemical staining with the anti-KLF5 Ab. The results suggest that KLF5 protein is generally weak in normal breast epithelial cells but strongly positive in breast tumors. Therefore, KLF5 expression is probably a good prognosis marker for breast cancer.
  
Entity Prostate cancer
Disease The KLF5 gene is deleted in about 33% prostate cancer cell lines/xenografts. Consistently, KLF5 mRNA is down-regulated in these samples compared to three immortalized prostate epithelial cell lines. In PC-3 prostate cancer cell line in which KLF5 mRNA is at normal high level, KLF5 protein is excessively degraded by over-expression of WWP1. KLF5 protein is highly expressed in normal prostate epithelial cells (Figure 5). Forced expression of KLF5 inhibits DU145 and 22Rv1 prostate cancer cell growth in vitro. In contrast, KLF5 knock-down decreases RWPE1 immortalized prostate epithelial cell growth in vitro. These results suggest that KLF5 may play a context dependent role in prostate cancer.
 
  
Entity Bladder cancer
Disease KLF5 mRNA is down-regulated in several bladder cancer cell lines. In TSu-Pr1 cell line, KLF5 over-expression promotes tumorigenesis in SCID mice. Consistently, KLF5 promotes cell cycle progression from G1 to S phase. Interestingly, KLF5 appears to promote tumor angiogenesis. Microarray analysis identified a number of angiogenic factors that are potentially regulated by KLF5, including HBP17, TGFa, and PDGFa. These findings suggest that the KLF5 transcription factor may play an oncogenic role in bladder cancer.
 
  
Entity Intestinal and colon cancer
Disease Down-regulation of KLF5 may be an early event in intestinal tumorigenesis. Expression of KLF5 in non-transformed intestinal epithelial cells enhances cell growth; however, KLF5 inhibits cell growth in colon cancer cell lines. Another group found that all-trans retinoic acid inhibits intestinal epithelial cell growth in vitro through inhibiting KLF5 expression. At the same time, lipopolysaccharide (LPS) induces proinflammatory response in intestinal epithelial cells through inducing KLF5 expression. These findings suggest that KLF5 may play an important but yet to be identified role in intestinal and colon cancer.
  
Entity Esophagus cancer
Disease KLF5 is expressed in proliferating cells of the gastrointestinal tract, including the esophagus. Expression of KLF5 in a poorly differentiated esophageal squamous cancer cell line TE2 inhibits proliferation and invasion, decreases viability after treatment with hydrogen peroxide and UV irradiation, and increases anoikis. KLF5 upregulates the cdk inhibitor p21(waf1/cip1) and pro-apoptotic protein BAX following UV irradiation.
  
Entity Skin cancer
Disease KLF5 is expressed predominantly in the basal layers of the developing epidermis, in the basal layers of cells of the inner root sheath, and in matrix cells of adult human hair follicles. In a transgenic mouse model, KLF5 over-expression in the basal layers of the epidermis causes abnormal epidermal development and differentiation. KLF5 over-expression may decrease the proliferation of stem cell populations of bulge keratinocytes.
  
Entity Cardiovascular remodeling
Disease KLF5 hemizygous knock-out mice reduce cardiac hypertrophy and interstitial fibrosis upon infusion of angiotensin II. Additionally, KLF5 may play a role in antherosclerosis and restenosis through regulating vascular smooth muscle cells.
  

Bibliography

-
 
Regulation of platelet-derived growth factor-A chain by Kruppel-like factor 5: new pathway of cooperative activation with nuclear factor-kappaB.
Aizawa, K., Suzuki, T., Kada, N., Ishihara, A., Kawai-Kowase, K., Matsumura, T., Sasaki, K., Munemasa, Y., Manabe, I., Kurabayashi, M., Collins, T., and Nagai, R.
J Biol Chem 2004; 279: 70-76.
PMID 14573617
 
Intestinal tumor progression is associated with altered function of KLF5.
Bateman, N. W., Tan, D., Pestell, R. G., Black, J. D., and Black, A. R.
J Biol Chem 2004; 279: 12093-12101.
PMID 14726538
 
Kruppel-like factor 5 is an important mediator for lipopolysaccharide-induced proinflammatory response in intestinal epithelial cells.
Chanchevalap, S., Nandan, M. O., McConnell, B. B., Charrier, L., Merlin, D., Katz, J. P., and Yang, V. W.
Nucleic Acids Res 2006; 34: 1216-1223.
PMID 16500892
 
KLF5 promotes cell proliferation and tumorigenesis through gene regulationin the TSU-Pr1 human bladder cancer cell line.
Chen, C., Benjamin, M. S., Sun, X., Otto, K. B., Guo, P., Dong, X. Y., Bao, Y., Zhou, Z., Cheng, X., Simons, J. W., and Dong, J. T.
Int J Cancer 2006; 118: 1346-1355.
PMID 16184550
 
KLF5 is frequently deleted and down-regulated but rarely mutated in prostate cancer.
Chen, C., Bhalala, H. V., Vessella, R. L., and Dong, J. T.
Prostate 2003; 55: 81-88.
PMID 12661032
 
Ubiquitin-proteasome degradation of KLF5 transcription factor in cancer and untransformed epithelial cells.
Chen, C., Sun, X., Ran, Q., Wilkinson, K. D., Murphy, T. J., Simons, J. W., and Dong, J. T.
Oncogene 2005; 24: 3319-3327.
PMID 15735697
 
Opposing effects of Kruppel-like factor 4 (gut-enriched Kruppel-like factor) and Kruppel-like factor 5 (intestinal-enriched Kruppel-like factor) on the promoter of the Kruppel-like factor 4 gene.
Dang, D. T., Zhao, W., Mahatan, C. S., Geiman, D. E., and Yang, V. W;
Nucleic Acids Res 2002; 30: 2736-2741.
PMID 12087155
 
The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.
Matsumura, T., Suzuki, T., Aizawa, K., Munemasa, Y., Muto, S., Horikoshi, M., and Nagai, R.
J Biol Chem 2005; 280: 12123-12129.
PMID 15668237
 
Positive and negative regulation of the cardiovascular transcription factor KLF5 by p300 and the oncogenic regulator SET through interaction and acetylation on the DNA-binding domain.
Miyamoto, S., Suzuki, T., Muto, S., Aizawa, K., Kimura, A., Mizuno, Y., Nagino, T., Imai, Y., Adachi, N., Horikoshi, M., and Nagai, R.
Mol Cell Biol 2003; 23: 8528-8541.
PMID 14612398
 
Downregulation and growth inhibitory effect of epithelial-type Kruppel-like transcription factor KLF4, but not KLF5, in bladder cancer.
Ohnishi, S., Ohnami, S., Laub, F., Aoki, K., Suzuki, K., Kanai, Y., Haga, K., Asaka, M., Ramirez, F., and Yoshida, T.
Biochem Biophys Res Commun 2003; 308: 251-256.
PMID 12901861
 
Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation.
Oishi, Y., Manabe, I., Tobe, K., Tsushima, K., Shindo, T., Fujiu, K., Nishimura, G., Maemura, K., Yamauchi, T., Kubota, N., Suzuki, R., Kitamura, T., Akira, S., Kadowaki, T., and Nagai, R.
Cell Metab 2005; 1: 27-39.
PMID 16054042
 
Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling.
Shindo, T., Manabe, I., Fukushima, Y., Tobe, K., Aizawa, K., Miyamoto, S., Kawai-Kowase, K., Moriyama, N., Imai, Y., Kawakami, H., Nishimatsu, H., Ishikawa, T., Suzuki, T., Morita, H., Maemura, K., Sata, M., Hirata, Y., Komukai, M., Kagechika, H., Kadowaki, T., Kurabayashi, M., and Nagai, R.
Nat Med 2002; 8: 856-863.
PMID 12101409
 
Epidermal and craniofacial defects in mice overexpressing Klf5 in the basal layer of the epidermis.
Sur, I., Rozell, B., Jaks, V., Bergstrom, A., and Toftgard, R.
J Cell Sci 2006; 119: 3593-3601.
PMID 16912082
 
Human Kruppel-like factor5/KLF5: synergy with NF-kappaB/Rel factors and expression in human skin and hair follicles.
Sur, I., Unden, A. B., and Toftgard, R.
Eur J Cell Biol 2002; 81: 323-334.
PMID 12113473
 
Regulation of T-cell receptor D beta 1 promoter by KLF5 through reiterated GC-rich motifs.
Yang, X. O., Doty, R. T., Hicks, J. S., and Willerford, D. M.
Blood 2003; 101: 4492-4499.
PMID 12576331
 
KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells.
Yang, Y., Goldstein, B. G., Chao, H. H., and Katz, J. P.
Cancer Biol Ther 2005; 4: 1216-1221.
PMID 16357509
 
Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function.
Zhang, Z. and Teng, C. T.
Nucleic Acids Res 2003; 31: 2196-2208.
PMID 12682370
 

Citation

This paper should be referenced as such :
Dong, JT ; Zhou, Y ; Chen, C
KLF5 (Kruppel-like factor 5 (intestinal))
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1):19-22.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/KLF5ID41074ch13q21.html


External links

Nomenclature
HGNC (Hugo)KLF5   6349
Cards
AtlasKLF5ID41074ch13q21
Entrez_Gene (NCBI)KLF5  688  Kruppel-like factor 5 (intestinal)
AliasesBTEB2; CKLF; IKLF
GeneCards (Weizmann)KLF5
Ensembl hg19 (Hinxton)ENSG00000102554 [Gene_View]  chr13:73629114-73651680 [Contig_View]  KLF5 [Vega]
Ensembl hg38 (Hinxton)ENSG00000102554 [Gene_View]  chr13:73629114-73651680 [Contig_View]  KLF5 [Vega]
ICGC DataPortalENSG00000102554
TCGA cBioPortalKLF5
AceView (NCBI)KLF5
Genatlas (Paris)KLF5
WikiGenes688
SOURCE (Princeton)KLF5
Genomic and cartography
GoldenPath hg19 (UCSC)KLF5  -     chr13:73629114-73651680 +  13q21.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)KLF5  -     13q21.3   [Description]    (hg38-Dec_2013)
EnsemblKLF5 - 13q21.3 [CytoView hg19]  KLF5 - 13q21.3 [CytoView hg38]
Mapping of homologs : NCBIKLF5 [Mapview hg19]  KLF5 [Mapview hg38]
OMIM602903   
Gene and transcription
Genbank (Entrez)AB030824 AF132818 AF287272 AK131397 AK296900
RefSeq transcript (Entrez)NM_001286818 NM_001730
RefSeq genomic (Entrez)NC_000013 NC_018924 NT_024524 NW_004929388
Consensus coding sequences : CCDS (NCBI)KLF5
Cluster EST : UnigeneHs.508234 [ NCBI ]
CGAP (NCI)Hs.508234
Alternative Splicing GalleryENSG00000102554
Gene ExpressionKLF5 [ NCBI-GEO ]   KLF5 [ EBI - ARRAY_EXPRESS ]   KLF5 [ SEEK ]   KLF5 [ MEM ]
Gene Expression Viewer (FireBrowse)KLF5 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)688
GTEX Portal (Tissue expression)KLF5
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13887 (Uniprot)
NextProtQ13887  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13887
Splice isoforms : SwissVarQ13887 (Swissvar)
PhosPhoSitePlusQ13887
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)zf-C2H2 (PF00096)   
Domain families : Pfam (NCBI)pfam00096   
Domain families : Smart (EMBL)ZnF_C2H2 (SM00355)  
DMDM Disease mutations688
Blocks (Seattle)KLF5
PDB (SRS)2EBT   
PDB (PDBSum)2EBT   
PDB (IMB)2EBT   
PDB (RSDB)2EBT   
Structural Biology KnowledgeBase2EBT   
SCOP (Structural Classification of Proteins)2EBT   
CATH (Classification of proteins structures)2EBT   
SuperfamilyQ13887
Human Protein AtlasENSG00000102554
Peptide AtlasQ13887
HPRD04212
IPIIPI00015934   IPI01012072   IPI01012474   IPI00816138   
Protein Interaction databases
DIP (DOE-UCLA)Q13887
IntAct (EBI)Q13887
FunCoupENSG00000102554
BioGRIDKLF5
STRING (EMBL)KLF5
ZODIACKLF5
Ontologies - Pathways
QuickGOQ13887
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  angiogenesis  protein binding  nucleoplasm  cytoplasm  Golgi apparatus  plasma membrane  transcription from RNA polymerase II promoter  microvillus assembly  regulation of microvillus assembly  skeletal muscle cell differentiation  intracellular membrane-bounded organelle  positive regulation of fat cell differentiation  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  intestinal epithelial cell development  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  angiogenesis  protein binding  nucleoplasm  cytoplasm  Golgi apparatus  plasma membrane  transcription from RNA polymerase II promoter  microvillus assembly  regulation of microvillus assembly  skeletal muscle cell differentiation  intracellular membrane-bounded organelle  positive regulation of fat cell differentiation  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  intestinal epithelial cell development  
REACTOMEQ13887 [protein]
REACTOME PathwaysR-HSA-381340 Transcriptional regulation of white adipocyte differentiation [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkKLF5
Wikipedia pathwaysKLF5
Orthology - Evolution
OrthoDB688
GeneTree (enSembl)ENSG00000102554
Phylogenetic Trees/Animal Genes : TreeFamKLF5
Homologs : HomoloGeneKLF5
Homology/Alignments : Family Browser (UCSC)KLF5
Gene fusions - Rearrangements
Fusion : MitelmanFBXL3/KLF5 [13q22.3/13q22.1]  [t(13;13)(q22;q22)]  
Fusion: TCGAFBXL3 13q22.3 KLF5 13q22.1 BRCA
Polymorphisms : SNP, variants
NCBI Variation ViewerKLF5 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLF5
dbVarKLF5
ClinVarKLF5
1000_GenomesKLF5 
Exome Variant ServerKLF5
ExAC (Exome Aggregation Consortium)KLF5 (select the gene name)
Genetic variants : HAPMAP688
Genomic Variants (DGV)KLF5 [DGVbeta]
Mutations
ICGC Data PortalKLF5 
TCGA Data PortalKLF5 
Broad Tumor PortalKLF5
OASIS PortalKLF5 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLF5 
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 KLF5
DgiDB (Drug Gene Interaction Database)KLF5
DoCM (Curated mutations)KLF5 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KLF5 (select a term)
intoGenKLF5
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)13:73629114-73651680  ENSG00000102554
CONAN: Copy Number AnalysisKLF5 
Mutations and Diseases : HGMDKLF5
OMIM602903   
MedgenKLF5
Genetic Testing Registry KLF5
NextProtQ13887 [Medical]
TSGene688
GENETestsKLF5
Huge Navigator KLF5 [HugePedia]
snp3D : Map Gene to Disease688
BioCentury BCIQKLF5
ClinGenKLF5
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD688
Chemical/Pharm GKB GenePA30139
Clinical trialKLF5
Miscellaneous
canSAR (ICR)KLF5 (select the gene name)
Probes
Litterature
PubMed139 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKLF5
EVEXKLF5
GoPubMedKLF5
iHOPKLF5
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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