WWOX (WW domain containing oxidoreductase)

2007-04-01 Teresa Druck , Hoda Hagrass , Kay Huebner Affiliation

BRT Rm. 940, 460 W. 12th Ave, Columbus, OH 43210

Identity

HGNC

WWOX

LOCATION

16q23.1

LOCUSID

51741

ALIAS

D16S432E,DEE28,EIEE28,FOR,FRA16D,HHCMA56,PRO0128,SCAR12,SDR41C1,WOX1

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

WWOX is comprised of 9 coding exons in a region of approximately one million base pairs that includes the common fragile site FRA16D.

Transcription

RT-PCR amplification of Wwox in normal and tumor cDNA samples has shown products apparently originating from alternative transcripts or transcript variants, respectively. Expressed truncated proteins have not been detected.

Pseudogene

None reported.

Proteins

Alignment of human (hWwox), mouse (Mwwox), fly (fWwox), mosquito (moWwox) and worm (ceWwox) Wwox proteins. The locations of the WW1 and WW2 domains are shown, as well as the predicted sites for nuclear localization, NADP binding, mitochondrial targeting, substrate binding and a proton acceptor.

Description

WWOX is a 414 amino acid protein that contains two WW domains and a short-chain dehydrogenase/reductase (SDR) domain.

Expression

WWOX is highly expressed in secretory epithelial cells of reproductive, endocrine and exocrine organs and is expressed in all or most other tissues at a lower level. The protein is not expressed or is expressed at low level in many tumor types, including breast, pancreatic, gastric, hepatocellular, ovarian, lung and prostate cancers. Loss of WWOX expression can be due to inactivation by promoter methylation, allelic deletion or a combination of these mechanisms.

Localisation

Cytoplasm, mitochondria.

Function

Contains an N-terminal group 1 WW domain that binds proteins with a PPXY motif. Reportedly interacts with p53, p73, JUN, ERBB4, Ap2alpha, Ap2gamma, Ezrin/VIL2, Ack1/TNK2. Probably involved in apoptosis, steroid (estrogen) metabolism and signaling pathways. Mice carrying a targeted deletion of the Wwox gene develop osteosarcomas in juvenile Wwox(-/-) and lung papillary carcinomas in adult Wwox(+/-) mice spontaneously. Wwox(+/-) mice develop significantly more ethyl nitrosourea-induced lung tumors and lymphomas than wild-type littermates.

Mutations

Somatic

Cancer cell lines from various tumor types, including ovarian, gastric and pancreatic, exhibit deletions within the WWOX gene, frequently in the introns surrounding exon 8.

Implicated in

Entity name

Breast cancer, esophageal and non-small cell lung cancer.

Disease

Breast, esophageal and non-small cell lung cancer show high LOH rates and low mutation rates. 27% of ER+ breast carcinomas versus 46% for ER- cases were completely negative for WWOX expression; when weakly WWOX expressing cases were included with negative cases the significance increased. Methylation of regulatory sequences in WWOX exon 1 distinguish breast cancer DNA from normal DNA and DNA from adjacent tissue. Treatment with 5-Aza-2-deoxycytidine to demethylate the WWOX promoter successfully restored WWOX expression in WWOX-deficient breast cancer cells.

Prognosis

In a sampling of 132 breast cancer tissues, high level WWOX expression was associated with better disease free survival.

Breakpoints

Location of the t(14;16)(q32.3;q23) translocation breakpoints falling within the WWOX gene in 3 multiple myeloma cell lines.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
16091150	2005	Characterization of the linkage disequilibrium structure and identification of tagging-SNPs in five DNA repair genes.	Allen-Brady K et al
17360458	2007	Targeted deletion of Wwox reveals a tumor suppressor function.	Aqeilan RI et al
11719429	2001	WWOX, the FRA16D gene, behaves as a suppressor of tumor growth.	Bednarek AK et al
16223882	2005	WWOX gene restoration prevents lung cancer growth in vitro and in vivo.	Fabbri M et al
17178850	2006	Physical association with WWOX suppresses c-Jun transcriptional activity.	Gaudio E et al
15998374	2005	Concordant loss of fragile gene expression early in breast cancer development.	Guler G et al
16225988	2006	Roles of FHIT and WWOX fragile genes in cancer.	Iliopoulos D et al
16438931	2006	PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction.	Jin C et al
11956080	2002	Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma.	Kuroki T et al
15073125	2004	The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis.	Kuroki T et al
15064722	2004	WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins.	Ludes-Meyers JH et al
16288044	2005	Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox.	Mahajan NP et al
16941225	2006	WWOX protein expression in normal human tissues.	Nunez MI et al
11572989	2001	WWOX: a candidate tumor suppressor gene involved in multiple tumor types.	Paige AJ et al
15266310	2004	Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma.	Park SW et al
16152610	2006	Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas.	Pimenta FJ et al
16360296	2006	WWOX--the FRA16D cancer gene: expression correlation with breast cancer progression and prognosis.	Płuciennik E et al
16818616	2006	A role for the WWOX gene in prostate cancer.	Qin HR et al
10861292	2000	Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells.	Ried K et al
12591741	2003	WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer.	Yendamuri S et al
16116962	2005	Deletion and mutation of WWOX exons 6-8 in human non-small cell lung cancer.	Zhou Y et al

Other Information

Locus ID:

NCBI: 51741
MIM: 605131
HGNC: 12799
Ensembl: ENSG00000186153

Variants:

dbSNP: 51741
ClinVar: 51741
TCGA: ENSG00000186153
COSMIC: WWOX

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000186153	ENST00000355860	Q9NZC7
ENSG00000186153	ENST00000402655	Q9NZC7
ENSG00000186153	ENST00000406884	Q9NZC7
ENSG00000186153	ENST00000408984	Q9NZC7
ENSG00000186153	ENST00000539474	F5H3R5
ENSG00000186153	ENST00000566662	H3BMD1
ENSG00000186153	ENST00000566780	Q9NZC7
ENSG00000186153	ENST00000566780	A0A411HBC7
ENSG00000186153	ENST00000569332	H3BMD1
ENSG00000186153	ENST00000569818	Q9NZC7
ENSG00000186153	ENST00000620008	A0A087WZG5
ENSG00000186153	ENST00000627394	H3BMD1

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Signal Transduction	REACTOME	R-HSA-162582
Signaling by ERBB4	REACTOME	R-HSA-1236394
Nuclear signaling by ERBB4	REACTOME	R-HSA-1251985
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	REACTOME	R-HSA-8864260
Activation of the TFAP2 (AP-2) family of transcription factors	REACTOME	R-HSA-8866907
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	REACTOME	R-HSA-8866904

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37615513	2024	Remote modulation of WWOX by an intronic variant associated with survival of Chinese gastric cancer patients.	0
37615513	2024	Remote modulation of WWOX by an intronic variant associated with survival of Chinese gastric cancer patients.	0
37248434	2023	WWOX binds MERIT40 and modulates its function in homologous recombination, implications in breast cancer.	1
37324196	2023	WWOX Polymorphisms as Predictors of the Biochemical Recurrence of Localized Prostate Cancer after Radical Prostatectomy.	0
37897534	2023	Loss of fragile WWOX gene leads to senescence escape and genome instability.	1
37974179	2023	Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome.	0
38203337	2023	Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis.	1
37248434	2023	WWOX binds MERIT40 and modulates its function in homologous recombination, implications in breast cancer.	1
37324196	2023	WWOX Polymorphisms as Predictors of the Biochemical Recurrence of Localized Prostate Cancer after Radical Prostatectomy.	0
37897534	2023	Loss of fragile WWOX gene leads to senescence escape and genome instability.	1
37974179	2023	Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome.	0
38203337	2023	Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis.	1
33629514	2022	Expression of WW domain-containing oxidoreductase and its clinical implication in endometrial adenocarcinoma patients with metabolic syndrome.	0
34852950	2022	Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes.	5
35290621	2022	TGFα-EGFR pathway in breast carcinogenesis, association with WWOX expression and estrogen activation.	1

Citation

Teresa Druck ; Hoda Hagrass ; Kay Huebner

WWOX (WW domain containing oxidoreductase)

Atlas Genet Cytogenet Oncol Haematol. 2007-04-01

Online version: http://atlasgeneticsoncology.org/gene/508/wwox-(ww-domain-containing-oxidoreductase)