Targeted ablation of the WW domain-containing oxidoreductase tumor suppressor leads to impaired steroidogenesis.
The WW domain-containing oxidoreductase (WWOX) gene encodes a 46-kDa tumor suppressor. The Wwox protein contains two N-terminal WW domains that interact with several transcriptional activators containing proline-tyrosine motifs and a central short-chain dehydrogenase/reductase domain that has been suggested to play a role in steroid metabolism. Recently, we have shown that targeted deletion of the Wwox gene in mice leads to postnatal lethality and defects in bone growth. Here, we report that Wwox-deficient mice display impaired steroidogenesis. Mutant homozygous mice are born with gonadal abnormalities, including failure of Leydig cell development in testis and reduced theca cell proliferation in ovary. Furthermore, Wwox(-/-) mice displayed impaired gene expression of key steroidogenesis enzymes. Affymetrix microarray gene analysis revealed differentially expressed related genes in steroidogenesis in knockout mice testis and ovary as compared with control mice. These results demonstrate the essential requirement for the Wwox tumor suppressor in proper steroidogenesis.
Aqeilan
Rami I
RI
Department of Molecular Virology, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA. rami.aqeilan@osumc.edu
Hagan
John P
JP
de Bruin
Alain
A
Rawahneh
Maysoon
M
Salah
Zaidoun
Z
Gaudio
Eugenio
E
Siddiqui
Hasan
H
Volinia
Stefano
S
Alder
Hansjuerg
H
Lian
Jane B
JB
Stein
Gary S
GS
Croce
Carlo M
CM
D000818:Animals; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000002:abnormalities / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics* / Q000502:physiology; D010902:Pituitary Gland / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D013737:Testis / Q000002:abnormalities / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase
D013256:Steroids; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C428130:Wwox protein, mouse