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WIF1 (WNT inhibitory factor 1)

Written2012-04Irene Vassallo, Monika E Hegi
Laboratory of Brain Tumor Biology, Genetics, Lausanne University Hospital, Lausanne, Switzerland

(Note : for Links provided by Atlas : click)

Identity

Other aliasWIF-1
HGNC (Hugo) WIF1
LocusID (NCBI) 11197
Atlas_Id 44085
Location 12q14.3  [Link to chromosome band 12q14]
Location_base_pair Starts at 65444404 and ends at 65515346 bp from pter ( according to hg19-Feb_2009)  [Mapping WIF1.png]
 
  Figure 1. WIF1 genomic context.
Fusion genes
(updated 2016)
HMGA2 (12q14.3) / WIF1 (12q14.3)RPSAP52 (12q14.3) / WIF1 (12q14.3)TCF7L1 (2p11.2) / WIF1 (12q14.3)
WIF1 (12q14.3) / HMGA2 (12q14.3)

DNA/RNA

 
  Figure 2. A) WIF1 gene structure. Transcription unit 71007 bp, mRNA 2304 bp. B) Structure of human WIF1 promoter.
Description The human WIF1 gene is located on the chromosome 12q14.2 from 65444404 bp to 65515346 bp (from pter). It is oriented on the minus strand and comprises 10 exons spanning 71007 bp of genomic DNA. The first and the 10th exons are partially composed by untranslated regions.
Transcription The mRNA produced is 2304 bp long. The promoter region of WIF1 has been cloned and studied by Reguart et al. and its structure is shown in Figure 2B (Reguart et al., 2004). Regulatory elements in the WIF1 promoter comprise a TATA box and binding sites of the transcription factors: Engrailed, E2F, GLI-Kruppel, NF-κB, and MYC, as visualized in Figure 2B. The CpG island located upstream of the WIF1 transcriptional start site is prone to aberrant methylation in various tumor types. Hypermethylation of this region has been found to be responsible for WIF1 downregulation, suggestive of tumor suppressor properties in different cancer types.
Pseudogene No pseudogene known so far.

Protein

 
  Figure 3. WIF1 protein domains.
Description WIF1 is a protein of 379 aminoacids, composed of a signal peptide for extracellular secretion, a WIF domain, five EGF repeats and a hydrophilic C terminus (Figure 3).
The WIF domain is responsible for the binding with some of the WNT ligands (3a, 4, 5a, 7a, 9a, 11) and to olfactomedin 1, a protein involved in neuronal differentiation (Hsieh et al., 1999).
Expression In development WIF1 starts to be produced during somitogenesis and maintains its expression in adults mainly in the lung, heart, and at the cartilage-mesenchyme interface (data derived from Xenopus, zebrafish and mouse).
Localisation WIF1 is an extracellular secreted protein.
Function WIF1 is a secreted WNT inhibitor that works by sequestering soluble Wnt proteins. It prevents the interaction between WNT morphogens and their specific receptors (Figure 4). WIF1 has been shown to bind to agonists of both, the canonical and the non-canonical WNT pathway. In contrast to other inhibitors like DKKs that can inhibit only the β-catenin dependent pathway, WIF1 can block the activation of both the canonical and the non-canonical WNT signaling pathway (Kawano and Kypta, 2003). Recently has been shown by Malinauskas et al. that WIF1 has a modular mechanism of inhibition. The WIF domain is responsible for the binding of WNT1 with WNT ligands and the five EGF-like domains seems to be partially involved in the extracellular localization of WIF1. The essential formation of gradients of WNT morphogens during development is mediated by interaction of the EGF-like domains and some glycosaminoglycans, namely heparin and heparan sulfate (Malinauskas et al., 2011).
 
  Figure 4. WIF1 inhibition mechanism.
Homology The WIF1 gene is conserved in
- P. troglodytes (WIF1)
- C. lupus (WIF1)
- M. musculus (WIF1)
- R. norvegicus (WIF1)
- G. gallus (WIF1)
- D. rerio (WIF1)
- D. melanogaster (shf)

Mutations

Note WIF1 is rarely mutated in human cancer.
Somatic According to COSMIC (Catalogue of Somatic Mutations in Cancer) only 6 samples over 1103 sequenced human cancer specimens show mutations that lead to amminoacid missense substitution.
Genomic deletions of the region where WIF1 is located have instead been reported for 10% of glioblastoma samples (Lambiv et al., 2011).

Implicated in

Note
  
Entity Cervical cancer
Note WIF1 is downregulated by promoter hypermethylation in 87.5% of primary cervical cancer. Peritumoral WIF1 gene transfer induces apoptosis and inhibits growth and invasion (Ramachandran et al., 2011).
  
  
Entity Glioblastoma
Note WIF1 silencing is mediated by both deletion (7/69, 10%) and promoter hypermethylation (29/110, 26%). WIF1 re-expression abolishes tumorigenicity of glioblastoma cell lines potentially by inducing senescence (Lambiv et al., 2011).
  
  
Entity Primary non-small-cell lung carcinoma (NSCLC)
Note WIF1 is frequently downregulated and this downregulation is correlated with WIF1 promoter hypermethylation (Mazieres et al., 2004).
  
  
Entity Osteosarcoma
Note Hypermethylation of the WIF1 promoter is found in the majority of osteosarcoma cell lines tested and it correlates with WIF1 mRNA downregulation (Rubin et al., 2010).
  
  
Entity Hepatocellular carcinoma (HCC)
Note WIF1 is frequently downregulated through promoter hypermethylation (Deng et al., 2010).
  
  
Entity Mesothelioma
Note WIF-1 promoter methylation was reported from 73.9% of mesothelioma tissues and in 100% of tested mesothelioma cell lines (Kohno et al., 2010).
  
  
Entity Renal cell carcinoma (RCC)
Note WIF-1 is downregulated by promoter methylation and when re-expressed induces apoptosis in RCC cells (Kawakami et al., 2009).
  
  
Entity Bladder cancer
Note Epigenetic inactivation of WIF1 in bladder cancer deregulates WNT pathway activation. WIF1 re-expression induces a G1-arrest via p27 and p21 accumulation (Tang et al., 2009; Urakami et al., 2006).
  
  
Entity Esophageal adenocarcinoma (EAC)
Note Epigenetic alteration of WIF1 is an early event in the carcinogenesis of EAC. It's suggested to be involved in the progression from Barrett's esophagus (BE) to EAC thus WIF1 hypermethylation is proposed to be used as a diagnostic and predictive marker for increased EAC risk in BE patients. (Clément et al., 2008).
  
  
Entity Gastrointestinal cancers
Note WIF-1 expression has been reported to be downregulated in 80.0% of esophageal, 74.2% of gastric, 82.0% of colorectal, and 75% of pancreatic cancer tissues. WIF1 silencing, mediated by hypermethylation, is proposed to be an early event in colorectal carcinogenesis (Taniguchi et al., 2005).
  
  
Entity Breast cancer
Note 67% of the investigated invasive breast adenocarcinoma (Stages II or III) shows aberrant WIF1 promoter methylation (Ai et al., 2006).
  
  
Entity Salivary gland pleomorphic adenoma
Note WIF1 is rearranged resulting in a HMGA2/WIF1 fusion transcript. In consequence of this fusion WIF1 that in normal salivary gland tissue is highly expressed becomes downregulated. On the contrary, HMGA2 that in normal tissue is not expressed is strongly upregulated (Queimado et al., 2007).
  

Bibliography

Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer.
Ai L, Tao Q, Zhong S, Fields CR, Kim WJ, Lee MW, Cui Y, Brown KD, Robertson KD.
Carcinogenesis. 2006 Jul;27(7):1341-8. Epub 2006 Feb 25.
PMID 16501252
 
Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett's esophagus.
Clement G, Guilleret I, He B, Yagui-Beltran A, Lin YC, You L, Xu Z, Shi Y, Okamoto J, Benhattar J, Jablons D.
Cancer Sci. 2008 Jan;99(1):46-53. Epub 2007 Nov 13.
PMID 18005197
 
Epigenetic silencing of WIF-1 in hepatocellular carcinomas.
Deng Y, Yu B, Cheng Q, Jin J, You H, Ke R, Tang N, Shen Q, Shu H, Yao G, Zhang Z, Qin W.
J Cancer Res Clin Oncol. 2010 Aug;136(8):1161-7. Epub 2010 Jan 30.
PMID 20119713
 
A new secreted protein that binds to Wnt proteins and inhibits their activities.
Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, Nusse R, Dawid IB, Nathans J.
Nature. 1999 Apr 1;398(6726):431-6.
PMID 10201374
 
Functional significance of Wnt inhibitory factor-1 gene in kidney cancer.
Kawakami K, Hirata H, Yamamura S, Kikuno N, Saini S, Majid S, Tanaka Y, Kawamoto K, Enokida H, Nakagawa M, Dahiya R.
Cancer Res. 2009 Nov 15;69(22):8603-10. Epub 2009 Nov 3.
PMID 19887605
 
Secreted antagonists of the Wnt signalling pathway.
Kawano Y, Kypta R.
J Cell Sci. 2003 Jul 1;116(Pt 13):2627-34.
PMID 12775774
 
Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma.
Kohno H, Amatya VJ, Takeshima Y, Kushitani K, Hattori N, Kohno N, Inai K.
Oncol Rep. 2010 Aug;24(2):423-31.
PMID 20596629
 
The Wnt inhibitory factor 1 (WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence.
Lambiv WL, Vassallo I, Delorenzi M, Shay T, Diserens AC, Misra A, Feuerstein B, Murat A, Migliavacca E, Hamou MF, Sciuscio D, Burger R, Domany E, Stupp R, Hegi ME.
Neuro Oncol. 2011 Jul;13(7):736-47. Epub 2011 Jun 3.
PMID 21642372
 
Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.
Malinauskas T, Aricescu AR, Lu W, Siebold C, Jones EY.
Nat Struct Mol Biol. 2011 Jul 10;18(8):886-93. doi: 10.1038/nsmb.2081.
PMID 21743455
 
Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer.
Mazieres J, He B, You L, Xu Z, Lee AY, Mikami I, Reguart N, Rosell R, McCormick F, Jablons DM.
Cancer Res. 2004 Jul 15;64(14):4717-20.
PMID 15256437
 
WIF1, an inhibitor of the Wnt pathway, is rearranged in salivary gland tumors.
Queimado L, Lopes CS, Reis AM.
Genes Chromosomes Cancer. 2007 Mar;46(3):215-25.
PMID 17171686
 
Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo.
Ramachandran I, Thavathiru E, Ramalingam S, Natarajan G, Mills WK, Benbrook DM, Zuna R, Lightfoot S, Reis A, Anant S, Queimado L.
Oncogene. 2012 May 31;31(22):2725-37. doi: 10.1038/onc.2011.455. Epub 2011 Oct 17.
PMID 22002305
 
Cloning and characterization of the promoter of human Wnt inhibitory factor-1.
Reguart N, He B, Xu Z, You L, Lee AY, Mazieres J, Mikami I, Batra S, Rosell R, McCormick F, Jablons DM.
Biochem Biophys Res Commun. 2004 Oct 8;323(1):229-34.
PMID 15351726
 
Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma.
Rubin EM, Guo Y, Tu K, Xie J, Zi X, Hoang BH.
Mol Cancer Ther. 2010 Mar;9(3):731-41. Epub 2010 Mar 2.
PMID 20197388
 
WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells.
Tang Y, Simoneau AR, Liao WX, Yi G, Hope C, Liu F, Li S, Xie J, Holcombe RF, Jurnak FA, Mercola D, Hoang BH, Zi X.
Mol Cancer Ther. 2009 Feb;8(2):458-68. Epub 2009 Jan 27.
PMID 19174556
 
Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers.
Taniguchi H, Yamamoto H, Hirata T, Miyamoto N, Oki M, Nosho K, Adachi Y, Endo T, Imai K, Shinomura Y.
Oncogene. 2005 Nov 24;24(53):7946-52.
PMID 16007117
 
Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway.
Urakami S, Shiina H, Enokida H, Kawakami T, Tokizane T, Ogishima T, Tanaka Y, Li LC, Ribeiro-Filho LA, Terashima M, Kikuno N, Adachi H, Yoneda T, Kishi H, Shigeno K, Konety BR, Igawa M, Dahiya R.
Clin Cancer Res. 2006 Jan 15;12(2):383-91.
PMID 16428476
 

Citation

This paper should be referenced as such :
Vassallo, I ; Hegi, ME
WIF1 (WNT inhibitory factor 1)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(10):706-709.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/WIF1ID44085ch12q14.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Head and Neck: Salivary gland tumors: an overview


External links

Nomenclature
HGNC (Hugo)WIF1   18081
Cards
AtlasWIF1ID44085ch12q14
Entrez_Gene (NCBI)WIF1  11197  WNT inhibitory factor 1
AliasesWIF-1
GeneCards (Weizmann)WIF1
Ensembl hg19 (Hinxton)ENSG00000156076 [Gene_View]  chr12:65444404-65515346 [Contig_View]  WIF1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000156076 [Gene_View]  chr12:65444404-65515346 [Contig_View]  WIF1 [Vega]
ICGC DataPortalENSG00000156076
TCGA cBioPortalWIF1
AceView (NCBI)WIF1
Genatlas (Paris)WIF1
WikiGenes11197
SOURCE (Princeton)WIF1
Genetics Home Reference (NIH)WIF1
Genomic and cartography
GoldenPath hg19 (UCSC)WIF1  -     chr12:65444404-65515346 -  12q14.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)WIF1  -     12q14.2   [Description]    (hg38-Dec_2013)
EnsemblWIF1 - 12q14.2 [CytoView hg19]  WIF1 - 12q14.2 [CytoView hg38]
Mapping of homologs : NCBIWIF1 [Mapview hg19]  WIF1 [Mapview hg38]
OMIM605186   
Gene and transcription
Genbank (Entrez)AF122922 AK301818 AL711431 AY358344 BC018037
RefSeq transcript (Entrez)NM_007191
RefSeq genomic (Entrez)NC_000012 NC_018923 NT_029419 NW_004929384
Consensus coding sequences : CCDS (NCBI)WIF1
Cluster EST : UnigeneHs.284122 [ NCBI ]
CGAP (NCI)Hs.284122
Alternative Splicing GalleryENSG00000156076
Gene ExpressionWIF1 [ NCBI-GEO ]   WIF1 [ EBI - ARRAY_EXPRESS ]   WIF1 [ SEEK ]   WIF1 [ MEM ]
Gene Expression Viewer (FireBrowse)WIF1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)11197
GTEX Portal (Tissue expression)WIF1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y5W5   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9Y5W5  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9Y5W5
Splice isoforms : SwissVarQ9Y5W5
PhosPhoSitePlusQ9Y5W5
Domaine pattern : Prosite (Expaxy)EGF_1 (PS00022)    EGF_2 (PS01186)    EGF_3 (PS50026)    WIF (PS50814)   
Domains : Interpro (EBI)EGF-like_CS    EGF-like_dom    WIF    Wnt-inh   
Domain families : Pfam (Sanger)hEGF (PF12661)    WIF (PF02019)   
Domain families : Pfam (NCBI)pfam12661    pfam02019   
Domain families : Smart (EMBL)EGF (SM00181)  WIF (SM00469)  
Domain structure : Prodom (Prabi Lyon)WIF (PD013948)   
Conserved Domain (NCBI)WIF1
DMDM Disease mutations11197
Blocks (Seattle)WIF1
PDB (SRS)2D3J    2YGN    2YGO    2YGP    2YGQ   
PDB (PDBSum)2D3J    2YGN    2YGO    2YGP    2YGQ   
PDB (IMB)2D3J    2YGN    2YGO    2YGP    2YGQ   
PDB (RSDB)2D3J    2YGN    2YGO    2YGP    2YGQ   
Structural Biology KnowledgeBase2D3J    2YGN    2YGO    2YGP    2YGQ   
SCOP (Structural Classification of Proteins)2D3J    2YGN    2YGO    2YGP    2YGQ   
CATH (Classification of proteins structures)2D3J    2YGN    2YGO    2YGP    2YGQ   
SuperfamilyQ9Y5W5
Human Protein AtlasENSG00000156076
Peptide AtlasQ9Y5W5
HPRD05541
IPIIPI00001863   IPI01009621   IPI01010846   IPI01015507   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y5W5
IntAct (EBI)Q9Y5W5
FunCoupENSG00000156076
BioGRIDWIF1
STRING (EMBL)WIF1
ZODIACWIF1
Ontologies - Pathways
QuickGOQ9Y5W5
Ontology : AmiGOprotein binding  extracellular region  signal transduction  multicellular organism development  Wnt signaling pathway  Wnt-protein binding  negative regulation of Wnt signaling pathway  positive regulation of fat cell differentiation  
Ontology : EGO-EBIprotein binding  extracellular region  signal transduction  multicellular organism development  Wnt signaling pathway  Wnt-protein binding  negative regulation of Wnt signaling pathway  positive regulation of fat cell differentiation  
Pathways : BIOCARTAWNT Signaling Pathway [Genes]   
Pathways : KEGGWnt signaling pathway   
REACTOMEQ9Y5W5 [protein]
REACTOME Pathways3772470 [pathway]   
NDEx NetworkWIF1
Atlas of Cancer Signalling NetworkWIF1
Wikipedia pathwaysWIF1
Orthology - Evolution
OrthoDB11197
GeneTree (enSembl)ENSG00000156076
Phylogenetic Trees/Animal Genes : TreeFamWIF1
HOVERGENQ9Y5W5
HOGENOMQ9Y5W5
Homologs : HomoloGeneWIF1
Homology/Alignments : Family Browser (UCSC)WIF1
Gene fusions - Rearrangements
Fusion : MitelmanHMGA2/WIF1 [12q14.3/12q14.3]  [t(12;12)(q14;q14)]  
Fusion : MitelmanTCF7L1/WIF1 [2p11.2/12q14.3]  [t(2;12)(p11;q14)]  
Fusion : COSMICHMGA2 [12q14.3]  -  WIF1 [12q14.3]  [fusion_1026]  [fusion_1027]  [fusion_1028]  [fusion_1029]  [fusion_1030]  [fusion_1031]  [fusion_1032]  
[fusion_1033]  [fusion_1034]  [fusion_1035]  [fusion_1036]  [fusion_1037]  
Fusion: TCGATCF7L1 2p11.2 WIF1 12q14.3 BRCA
Fusion : TICdbHMGA2 [12q14.3]  -  WIF1 [12q14.3]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerWIF1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)WIF1
dbVarWIF1
ClinVarWIF1
1000_GenomesWIF1 
Exome Variant ServerWIF1
ExAC (Exome Aggregation Consortium)WIF1 (select the gene name)
Genetic variants : HAPMAP11197
Genomic Variants (DGV)WIF1 [DGVbeta]
DECIPHER (Syndromes)12:65444404-65515346  ENSG00000156076
CONAN: Copy Number AnalysisWIF1 
Mutations
ICGC Data PortalWIF1 
TCGA Data PortalWIF1 
Broad Tumor PortalWIF1
OASIS PortalWIF1 [ Somatic mutations - Copy number]
Cancer Gene: CensusWIF1 
Somatic Mutations in Cancer : COSMICWIF1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDWIF1
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 WIF1
DgiDB (Drug Gene Interaction Database)WIF1
DoCM (Curated mutations)WIF1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)WIF1 (select a term)
intoGenWIF1
NCG5 (London)WIF1
Cancer3DWIF1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605186   
Orphanet
MedgenWIF1
Genetic Testing Registry WIF1
NextProtQ9Y5W5 [Medical]
TSGene11197
GENETestsWIF1
Huge Navigator WIF1 [HugePedia]
snp3D : Map Gene to Disease11197
BioCentury BCIQWIF1
ClinGenWIF1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD11197
Chemical/Pharm GKB GenePA38291
Clinical trialWIF1
Miscellaneous
canSAR (ICR)WIF1 (select the gene name)
Probes
Litterature
PubMed94 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineWIF1
EVEXWIF1
GoPubMedWIF1
iHOPWIF1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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