XAF1 (XIAP associated factor-1)

Identity

Other names	HSXIAPAF1
	BIRC4BP
Hugo	XAF1
Location	17p13.2
Local_order	Telomeric to TP53 gene (17p13.1)

Note	XAF1 not approved by the HUGO Gene Nomenclature Committee (HGNC).

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

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.

External links

	Nomenclature
Hugo	-
GDB	XAF1
Entrez_Gene	XAF1  54739  XIAP associated factor-1
	Cards
Atlas	XAF1ID44095ch17p13
GeneCards	XAF1
Ensembl	XAF1 [Search_View]   ENSG00000132530 [Gene_View]
Genatlas	XAF1
GeneLynx	XAF1
eGenome	XAF1
euGene	54739
	Genomic and cartography
GoldenPath	XAF1  -  17p13.2   chr17:6599880-6619686 +  17p13.2   [Description]    (hg18-Mar_2006)
Ensembl	XAF1 - 17p13.2 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	XAF1
	Gene and transcription
Genbank	AK056908 [ ENTREZ ]
Genbank	AK091799 [ ENTREZ ]
Genbank	AK292710 [ ENTREZ ]
Genbank	BC032776 [ ENTREZ ]
Genbank	BC058017 [ ENTREZ ]
RefSeq	NM_017523 [ SRS ]    NM_017523 [ ENTREZ ]
RefSeq	NM_199139 [ SRS ]    NM_199139 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ]    AC_000060 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ]    NC_000017 [ ENTREZ ]
RefSeq	NT_010718 [ SRS ]    NT_010718 [ ENTREZ ]
RefSeq	NW_926584 [ SRS ]    NW_926584 [ ENTREZ ]
AceView	XAF1 AceView - NCBI
Unigene	Hs.441975 [ SRS ]    Hs.441975 [ NCBI ]     HS441975 [ spliceNest ]
Fast-db	2459 (alternative variants)
	Protein : pattern, domain, 3D structure
HPRD	06978
	Protein Interaction databases
	Polymorphism : SNP, mutations, diseases
OMIM	606717    [ map ]
GENECLINICS	606717
SNP	XAF1 [dbSNP-NCBI]
SNP	NM_017523 [SNP-NCI]
SNP	NM_199139 [SNP-NCI]
SNP	XAF1 [GeneSNPs - Utah]  XAF1] [HGBASE - SRS]
HAPMAP	XAF1 [HAPMAP]
HGMD	-
	General knowledge
Family Browser	XAF1 [UCSC Family Browser]
SOURCE	NM_017523
SOURCE	NM_199139
SMD	Hs.441975
SAGE	Hs.441975
GO	zinc ion binding [Amigo]  zinc ion binding
PubGene	XAF1
TreeFam	-
CTD	54739 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	XAF1 Related clones (RZPD - Berlin)
	PubMed
PubMed	20 Pubmed reference(s) in LocusLink

Bibliography

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	01-2008	Stéphanie 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

Citation

This paper should be referenced as such :

Plenchette S, Fong WG, Korneluk RG . XAF1 (XIAP associated factor-1). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/XAF1ID44095ch17p13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:28:04 2008