Aqeilan Rami I, Hagan John P, de Bruin Alain, Rawahneh Maysoon, Salah Zaidoun, Gaudio Eugenio, Siddiqui Hasan, Volinia Stefano, Alder Hansjuerg, Lian Jane B, Stein Gary S, Croce Carlo M
Department of Molecular Virology, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.
Endocrinology. 2009 Mar;150(3):1530-5. doi: 10.1210/en.2008-1087. Epub 2008 Oct 30.
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.
含WW结构域的氧化还原酶（WWOX）基因编码一种46 kDa的肿瘤抑制因子。WWOX蛋白包含两个N端WW结构域，可与多个含有脯氨酸 - 酪氨酸基序的转录激活因子相互作用，以及一个位于中央的短链脱氢酶/还原酶结构域，该结构域被认为在类固醇代谢中起作用。最近，我们发现小鼠中Wwox基因的靶向缺失会导致出生后死亡和骨骼生长缺陷。在此，我们报告Wwox基因缺陷型小鼠表现出类固醇生成受损。突变纯合小鼠出生时伴有性腺异常，包括睾丸中Leydig细胞发育失败和卵巢中卵泡膜细胞增殖减少。此外，Wwox（-/-）小鼠关键类固醇生成酶的基因表达受损。与对照小鼠相比，Affymetrix微阵列基因分析揭示了基因敲除小鼠睾丸和卵巢中类固醇生成相关基因的差异表达。这些结果证明了Wwox肿瘤抑制因子在正常类固醇生成中的必需性。
