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XAF1 (XIAP associated factor-1)

Written2008-01Stéphanie Plenchette, Wai Gin Fong, Robert G Korneluk
Children's Hospital of Eastern Ontario, Apoptosis Research Centre, Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)BIRC4BP
XIAPAF1
HSXIAPAF1
Other alias
HGNC (Hugo) XAF1
LocusID (NCBI) 54739
Atlas_Id 44095
Location 17p13.1  [Link to chromosome band 17p13]
Location_base_pair Starts at 6755837 and ends at 6775645 bp from pter ( according to hg19-Feb_2009)  [Mapping XAF1.png]
Local_order Telomeric to TP53 gene (17p13.1)
Fusion genes
(updated 2016)
XAF1 (17p13.1) / FAM64A (17p13.2)XAF1 (17p13.1) / SLC8A1 (2p22.1)

DNA/RNA

 
  Schematic diagram of the XAF1 gene comprising 8 exons (in grey) and transcript variants. The sizes in base pairs (bp) of exons (above) and introns (below) are shown. (*) indicates the positions of the stop codons.
Description The XAF1 gene exists as a single copy in the human genome; it contains 8 exons and was predicted to span over approximately 18 kb of the genomic DNA.
Transcription Five isoforms of XAF1 cDNA have been identified and are expressed in a cell and tissue type specific-manner:
The original XAF1, also called XAF1(A) (CDS: 906nt)
The XAF1(B) isoform (CDS: 849nt); lacks exon 3
The XAF1(C) isoform (CDS: 495nt); contains exon 4b and a new stop codon
The XAF1(D) isoform (CDS: 426nt); lacks exons 4b and 5 (new stop codon in exon 6)
The XAF1(E) isoform (CDS: 369nt); lacks exons 3, 4b and 5 (new stop codon in exon 6)
With Northern blot analysis, at least four distinct transcripts sizes have been identified in Homo sapiens (3.9 kb, 4.5 kb, 6.0 kb and 7.0 kb). How these mRNA species relate to isoform variants is not known.
Pseudogene Not known

Protein

Description The full length XAF1 protein consists of 301 amino acids corresponding to a molecular weight of 33.411 kDa. The protein contains seven zinc fingers domains. The XAF1(B) isoform is predicted to lack the third N-terminal zinc finger of the previously described XAF1. The XAF1(C) is predicted to contain the first five amino-terminal zinc finger domains of the previously described XAF1 and also a unique 24 aa carboxy terminus. There is no evidence for XAF1 isoforms (C), (D) and (E) expression at the protein level.
Expression Normal tissue: ubiquitous and differential expression in normal tissues; highest in heart and ovary and lowest in brain and testis at mRNA levels. The XAF1 protein also displays differential protein expression profile within normal cell or tissue development including placenta and motoneurons.
Cancer: as opposed to normal cells, XAF1 is found either low or undetectable in tumor cell lines at both mRNA and protein levels. Expression varies also widely among different tumor cell lines. High levels of XAF1 protein were found in glioblastoma cells (SF-539) and ovarian cells (OVCAR-5). Detectable levels were found also in various gastric and colon cancer cell lines and also myeloma cells (U266).
Localisation Nuclear and cytoplasmic distribution
Function Tumor suppressor gene: loss of heterozygosity (LOH) found in 12 of 33 (36%) human primary colorectal carcinomas. The absence or reduced expression of XAF1 in cancer cell lines by genetic or epigenetic modifications have suggested a possible role in the suppression of development and/or progression of malignancy.
IAP antagonist: XAF1 exerts a proapoptotic effect by directly interacting with BIRC4/XIAP and antagonizing its anticaspase activity. XAF1 enhances XIAP E3 ligase activity towards BIRC5/Survivin through a complex and mediates Survivin down-regulation.
Interferon (IFN)-stimulated gene (ISG): XAF1 is an important mediator of IFN-induced sensitization to TNF-related apoptosis-inducing ligand (TRAIL) in cancer.
Increasing expression of XAF1 sensitizes cells to apoptosis-induced by various stimuli including etoposide, 5-FU, TRAIL, anti-Fas Ab, TNFalpha, UV, H2O2, gamma-irradiation.
Homology XAF1 shares high amino acid similarity with the zinc finger domains of FLN29 and TRAF6.

Mutations

Note Include genetic and epigenetic modification
Epigenetics Aberrant promoter hypermethylation in the 5' proximal region (from +3nt to -234 nt) in a variety of gastric, colon, bladder, kidney and prostate cancer cell lines and tumors.
Germinal Not known
Somatic No somatic mutations in tumor cell lines examined. LOH described in colon tumors.

Implicated in

Note
  
Entity Colorectal cancer, gastric cancer, urogenital cancer
Oncogenesis XAF1 is proposed to be a tumor suppressor gene. Correlation of reduction in XAF1 expression with stage and grade within gastric and colorectal tumors demonstrating that the loss of XAF1 contributes to tumorigenesis.
  

Bibliography

Degradation of survivin by the X-linked inhibitor of apoptosis (XIAP)-XAF1 complex.
Arora V, Cheung HH, Plenchette S, Micali OC, Liston P, Korneluk RG
The Journal of biological chemistry. 2007 ; 282 (36) : 26202-26209.
PMID 17613533
 
Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas.
Byun DS, Cho K, Ryu BK, Lee MG, Kang MJ, Kim HR, Chi SG
Cancer research. 2003 ; 63 (21) : 7068-7075.
PMID 14612497
 
Frequent alteration of XAF1 in human colorectal cancers: implication for tumor cell resistance to apoptotic stresses.
Chung SK, Lee MG, Ryu BK, Lee JH, Han J, Byun DS, Chae KS, Lee KY, Jang JY, Kim HJ, Chi SG
Gastroenterology. 2007 ; 132 (7) : 2459-2477.
PMID 17570219
 
Switch to full-length of XAF1 mRNA expression in prostate cancer cells by the DNA methylation inhibitor.
Fang X, Liu Z, Fan Y, Zheng C, Nilson S, Egevad L, Ekman P, Xu D
International journal of cancer. Journal international du cancer. 2006 ; 118 (10) : 2485-2489.
PMID 16353137
 
Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines.
Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG
Genomics. 2000 ; 70 (1) : 113-122.
PMID 11087668
 
Gene expression and promoter methylation of the XIAP-associated Factor 1 in renal cell carcinomas: correlations with pathology and outcome.
Kempkensteffen C, Hinz S, Schrader M, Christoph F, Magheli A, Krause H, Schostak M, Miller K, Weikert S
Cancer letters. 2007 ; 254 (2) : 227-235.
PMID 17449173
 
Identification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2L-induced apoptosis.
Leaman DW, Chawla-Sarkar M, Vyas K, Reheman M, Tamai K, Toji S, Borden EC
The Journal of biological chemistry. 2002 ; 277 (32) : 28504-28511.
PMID 12029096
 
Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses.
Lee MG, Huh JS, Chung SK, Lee JH, Byun DS, Ryu BK, Kang MJ, Chae KS, Lee SJ, Lee CH, Kim JI, Chang SG, Chi SG
Oncogene. 2006 ; 25 (42) : 5807-5822.
PMID 16909101
 
Identification of XAF1 as an antagonist of XIAP anti-Caspase activity.
Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG
Nature cell biology. 2001 ; 3 (2) : 128-133.
PMID 11175744
 
Low expression of XIAP-associated factor 1 in human colorectal cancers.
Ma TL, Ni PH, Zhong J, Tan JH, Qiao MM, Jiang SH
Chinese journal of digestive diseases. 2005 ; 6 (1) : 10-14.
PMID 15667552
 
XAF1 expression is significantly reduced in human melanoma.
Ng KC, Campos EI, Martinka M, Li G
The Journal of investigative dermatology. 2004 ; 123 (6) : 1127-1134.
PMID 15610524
 
Motoneuron resistance to apoptotic cell death in vivo correlates with the ratio between X-linked inhibitor of apoptosis proteins (XIAPs) and its inhibitor, XIAP-associated factor 1.
Perrelet D, Perrin FE, Liston P, Korneluk RG, MacKenzie A, Ferrer-Alcon M, Kato AC
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004 ; 24 (15) : 3777-3785.
PMID 15084658
 
The role of XAF1 in cancer.
Plenchette S, Cheung HH, Fong WG, LaCasse EC, Korneluk RG
Current opinion in investigational drugs (London, England : 2000). 2007 ; 8 (6) : 469-476.
PMID 17621877
 
Potent antitumor efficacy of XAF1 delivered by conditionally replicative adenovirus vector via caspase-independent apoptosis.
Qi R, Gu J, Zhang Z, Yang K, Li B, Fan J, Wang C, He Z, Qiao L, Lin Z, Liu XY
Cancer gene therapy. 2007 ; 14 (1) : 82-90.
PMID 17008933
 
Adjuvant whole abdominal intensity modulated radiotherapy (IMRT) for high risk stage FIGO III patients with ovarian cancer (OVAR-IMRT-01) - Pilot trial of a phase I/II study: study protocol.
Rochet N, Jensen AD, Sterzing F, Munter MW, Eichbaum MH, Schneeweiss A, Sohn C, Debus J, Harms W
BMC cancer. 2007 ; 7 : page 227.
PMID 18093313
 
All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer.
Wang J, Peng Y, Sun YW, He H, Zhu S, An X, Li M, Lin MC, Zou B, Xia HH, Jiang B, Chan AO, Yuen MF, Kung HF, Wong BC
Gastroenterology. 2006 ; 130 (3) : 747-758.
PMID 16530516
 
Xaf1 can cooperate with TNFalpha in the induction of apoptosis, independently of interaction with XIAP.
Xia Y, Novak R, Lewis J, Duckett CS, Phillips AC
Molecular and cellular biochemistry. 2006 ; 286 (1-2) : 67-76.
PMID 16432762
 
Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy.
Yang L, Cao Z, Yan H, Wood WC
Cancer research. 2003 ; 63 (20) : 6815-6824.
PMID 14583479
 
Identification of a novel splice variant of X-linked inhibitor of apoptosis-associated factor 1.
Yin W, Cheepala S, Clifford JL
Biochemical and biophysical research communications. 2006 ; 339 (4) : 1148-1154.
PMID 16343440
 
Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers.
Zou B, Chim CS, Zeng H, Leung SY, Yang Y, Tu SP, Lin MC, Wang J, He H, Jiang SH, Sun YW, Yu LF, Yuen ST, Kung HF, Wong BC
Gastroenterology. 2006 ; 131 (6) : 1835-1843.
PMID 17087954
 

Citation

This paper should be referenced as such :
Plenchette, S ; Fong, WG ; Korneluk, RG
XAF1 (XIAP associated factor-1)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5):397-399.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/XAF1ID44095ch17p13.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Lung: Translocations in Adenocarcinoma


External links

Nomenclature
HGNC (Hugo)XAF1   30932
Cards
AtlasXAF1ID44095ch17p13
Entrez_Gene (NCBI)XAF1  54739  XIAP associated factor 1
AliasesBIRC4BP; HSXIAPAF1; XIAPAF1
GeneCards (Weizmann)XAF1
Ensembl hg19 (Hinxton)ENSG00000132530 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000132530 [Gene_View]  chr17:6755837-6775645 [Contig_View]  XAF1 [Vega]
ICGC DataPortalENSG00000132530
TCGA cBioPortalXAF1
AceView (NCBI)XAF1
Genatlas (Paris)XAF1
WikiGenes54739
SOURCE (Princeton)XAF1
Genetics Home Reference (NIH)XAF1
Genomic and cartography
GoldenPath hg38 (UCSC)XAF1  -     chr17:6755837-6775645 +  17p13.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)XAF1  -     17p13.1   [Description]    (hg19-Feb_2009)
EnsemblXAF1 - 17p13.1 [CytoView hg19]  XAF1 - 17p13.1 [CytoView hg38]
Mapping of homologs : NCBIXAF1 [Mapview hg19]  XAF1 [Mapview hg38]
OMIM606717   
Gene and transcription
Genbank (Entrez)AK056908 AK091799 AK290276 AK292710 AK292848
RefSeq transcript (Entrez)NM_017523 NM_199139
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)XAF1
Cluster EST : UnigeneHs.441975 [ NCBI ]
CGAP (NCI)Hs.441975
Alternative Splicing GalleryENSG00000132530
Gene ExpressionXAF1 [ NCBI-GEO ]   XAF1 [ EBI - ARRAY_EXPRESS ]   XAF1 [ SEEK ]   XAF1 [ MEM ]
Gene Expression Viewer (FireBrowse)XAF1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)54739
GTEX Portal (Tissue expression)XAF1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6GPH4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6GPH4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6GPH4
Splice isoforms : SwissVarQ6GPH4
PhosPhoSitePlusQ6GPH4
Domaine pattern : Prosite (Expaxy)ZF_TRAF (PS50145)   
Domains : Interpro (EBI)XAF1    Znf_TRAF   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)XAF1
DMDM Disease mutations54739
Blocks (Seattle)XAF1
PDB (SRS)2LXW   
PDB (PDBSum)2LXW   
PDB (IMB)2LXW   
PDB (RSDB)2LXW   
Structural Biology KnowledgeBase2LXW   
SCOP (Structural Classification of Proteins)2LXW   
CATH (Classification of proteins structures)2LXW   
SuperfamilyQ6GPH4
Human Protein AtlasENSG00000132530
Peptide AtlasQ6GPH4
HPRD06978
IPIIPI00013986   IPI00395806   IPI00889535   IPI00889533   IPI00796968   IPI00788966   IPI00889586   IPI00903158   IPI00952715   IPI00952596   
Protein Interaction databases
DIP (DOE-UCLA)Q6GPH4
IntAct (EBI)Q6GPH4
FunCoupENSG00000132530
BioGRIDXAF1
STRING (EMBL)XAF1
ZODIACXAF1
Ontologies - Pathways
QuickGOQ6GPH4
Ontology : AmiGOnucleus  mitochondrion  cytosol  apoptotic process  zinc ion binding  negative regulation of protein complex assembly  response to interferon-beta  type I interferon signaling pathway  
Ontology : EGO-EBInucleus  mitochondrion  cytosol  apoptotic process  zinc ion binding  negative regulation of protein complex assembly  response to interferon-beta  type I interferon signaling pathway  
REACTOMEQ6GPH4 [protein]
REACTOME PathwaysR-HSA-909733 [pathway]   
NDEx NetworkXAF1
Atlas of Cancer Signalling NetworkXAF1
Wikipedia pathwaysXAF1
Orthology - Evolution
OrthoDB54739
GeneTree (enSembl)ENSG00000132530
Phylogenetic Trees/Animal Genes : TreeFamXAF1
HOVERGENQ6GPH4
HOGENOMQ6GPH4
Homologs : HomoloGeneXAF1
Homology/Alignments : Family Browser (UCSC)XAF1
Gene fusions - Rearrangements
Fusion : MitelmanXAF1/FAM64A [17p13.1/17p13.2]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerXAF1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)XAF1
dbVarXAF1
ClinVarXAF1
1000_GenomesXAF1 
Exome Variant ServerXAF1
ExAC (Exome Aggregation Consortium)XAF1 (select the gene name)
Genetic variants : HAPMAP54739
Genomic Variants (DGV)XAF1 [DGVbeta]
DECIPHERXAF1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisXAF1 
Mutations
ICGC Data PortalXAF1 
TCGA Data PortalXAF1 
Broad Tumor PortalXAF1
OASIS PortalXAF1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICXAF1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDXAF1
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 XAF1
DgiDB (Drug Gene Interaction Database)XAF1
DoCM (Curated mutations)XAF1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)XAF1 (select a term)
intoGenXAF1
NCG5 (London)XAF1
Cancer3DXAF1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606717   
Orphanet
MedgenXAF1
Genetic Testing Registry XAF1
NextProtQ6GPH4 [Medical]
TSGene54739
GENETestsXAF1
Target ValidationXAF1
Huge Navigator XAF1 [HugePedia]
snp3D : Map Gene to Disease54739
BioCentury BCIQXAF1
ClinGenXAF1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD54739
Chemical/Pharm GKB GenePA162409299
Clinical trialXAF1
Miscellaneous
canSAR (ICR)XAF1 (select the gene name)
Probes
Litterature
PubMed65 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineXAF1
EVEXXAF1
GoPubMedXAF1
iHOPXAF1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Aug 1 17:40:09 CEST 2017

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