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Targeted Ablation of the WW Domain-Containing Oxidoreductase Tumor Suppressor Leads to Impaired Steroidogenesis

Department of Molecular Virology, Immunology and Medical Genetics (R.I.A., J.P.H., A.d.B., M.R., E.G., H.S., S.V., H.A., S.V., H.A., C.M.C.), Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210; Lautenberg Center for General and Tumor Immunology (R.I.A., Z.S.), The Institute for Medical Research - Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; and Department of Cell Biology and Cancer Center (J.B.L., G.S.S.), University of Massachusetts Medical School, Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Rami I. Aqeilan, Human Cancer Genetics Program, Ohio State University-Biomedical Research Tower, Room 1088, 460 West 12th Avenue, Columbus, Ohio 43210. E-mail: rami.aqeilan{at}osumc.edu.

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.

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