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FLASH GENE

Symbol

WWOX

contributors: mct/npt/pgu - updated : 13-01-2013

HGNC name	WW domain containing oxidoreductase
HGNC id	12799

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	1113.01 kb     9 Exon(s)

10 Kb 5' upstream gene genomic sequence study

text structure

extending over a region of 1mb

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D16S518 - WWOX - D16S3029 - D16S3096 - D16S504 - qter
Text	see TSG16A

regionally located

in the D16S516 deleted region

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_130791 6 splicing 735 NP_570607 - 189 tumoral tissu 2009 19465938 also called FORI-Variant 2 a partial deletion of exon 9 with a unique C-terminus NM_016373 9 splicing 2264 NP_057457 46 414 normal or tumoral tissu 2009 19465938 also called FORII NM_130844 1 splicing 545 NP_570859 - 36 tumoral tissu 2009 19465938 also called FORIII-Variant 3 lack exons 6,7,8 an out-of-frame deletion of exon 5-8 and frame-shift at the C-terminus

EXPRESSION

Type

widely

constitutive of

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic spleen       highly Endocrine thyroid       highly Lymphoid/Immune thymus         Nervous brain           nerve         Reproductive female system breast mammary gland   highly   female system ovary     highly   male system testis     highly   male system prostate     highly Respiratory lung         Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Muscular striatum skeletal

cell lineage
cell lines	breast cancer cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	two N-terminal WW domains :
	first WW domain has two conserved tryptophans
	the second WW domain has only one), with caspase-recognition motif QETD (amino acid 65-68) in the second WW domain
	a nuclear localization signal (NLS)
	a central short-chain dehydrogenase/reductase domain
	a typical C-terminal short-chain alcohol dehydrogenase
	reductase (SDR) domain

HOMOLOGY

interspecies

homolog to murine Wox1

Homologene

FAMILY

short-chain dehydrogenases/reductases (SDR) family

CATEGORY

enzyme , transport

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,endoplasmic reticulum ,rough,smooth
	intracellular,cytoplasm,organelle,Golgi
	intracellular,nucleus

basic FUNCTION	potentially involved in steroid metabolism
	playing a role in protein-protein interaction
	target of FRA16D and potent suppressor of tumor
	inducing cell growth inhibition and apoptosis in lung cancer cells
	involved in embryonic development and differentiation, and probably having a homeostatic role in normal cell-cycle progression in concert with TP53, TP73, ERBB4 and other transcription factors
	playing a protective role where aberrant expression, as a result of breakage at the associated fragile site, could contribute directly to cancer progression
	required in postnatal survival, growth, and metabolism and may play a central role in regulation of bone tissue formation
	suppresses prostate cancer cell growth through modulation of ERBB2-mediated androgen receptor signaling
	playing an important role in fundamental cellular processes, including survival, growth, bone metabolism, and neoplastic transformation
	tumor suppressor gene involved in apoptosis
	important proapoptotic protein
	inhibitor of the Wnt/beta-catenin pathway and would act, at least in part, by preventing the nuclear import of the Dvl proteins
	suppresses the transactivation function of several transcription factors implied in neoplasia by sequestering them in the cytoplasm
	participates in a number of cellular processes including growth, differentiation, apoptosis, and tumor suppression
	involved in numerous important signal pathways for bone and germ-cell development, cellular and animal growth and death, transcriptional control and suppression of cancer development
	critical role in preventing tumorigenesis in breast cancer

CELLULAR PROCESS	cell life, cell death/apoptosis
	protein, post translation, targeting

PHYSIOLOGICAL PROCESS

mitochondrial transport

text	putatively involved in regulation of apoptosis

PATHWAY

metabolism

other

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	with TP73 (increasing WWOX proapoptotic activity)
	interacts with proline-tyrosine rich motif-containing proteins
	physically associates with RUNX2, the principal transcriptional regulator of osteoblast differentiation, and on osteocalcin chromatin (functionally suppresses RUNX2 transactivation ability in osteoblasts)
	interacting with ERBB4
	associates with proline-rich motifs of SIMPLE and EZRIN and with proteins lacking the PPXY motif such as TP53 and c-Jun N-terminal kinase (JNK)

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

EIEE28 , SCAEMR

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in primary acute leukemia often in association with FHIT alterations tumoral     --over   in breast cancer tumoral   LOH     in ovarian cancer cells and different cell lines tumoral     --low   in non-invasive breast and gastric cancer tissues tumoral   deletion     in adenocarcinomas of colon, stomach, lung, ovary, prostate carcinoma tumoral   translocation     in multiple myeloma, translocation t(14;16) (q32;q23) tumoral     --low   in primary oral squamous cell carcinomas, and in prostate carcinoma tumoral   LOH     in multiple myeloma with poor prognosis tumoral     --low   is an important step that might increase the vulnerability to the carcinogenesis process in papillary thyroid carcinomas constitutional germinal mutation       associated with a 46,XY DSD

Susceptibility

to low plasma HDL cholesterol an to coronary artery disease to autism spectrum disorder (ASD)

Variant & Polymorphism other	variant associated to low plasma HDL cholesterol
	copy-number variants (CNVs) in WWOX contribute significantly to autism spectrum disorder (ASD) risk

Candidate gene	target for DNA instability at 16q23.2
	role in human gonad development
Marker
Therapy target	potential target for lung cancer prevention and therapy

ANIMAL & CELL MODELS

Wwox KO mouse models showing gonadal abnormalities