Matsuzawa-Watanabe Yumiko, Inoue Jun-Ichiro, Semba Kentaro
Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Oncogene. 2003 Sep 11;22(39):7900-4. doi: 10.1038/sj.onc.1206717.
The Wilms' tumor 1 (WT1) and sex-determining region of the Y chromosome (SRY) genes are essential for development of the mammalian gonads and mutations in these genes are associated with gonadal dysgenesis in humans. The SRY gene encodes a transcription factor with one high-mobility group (HMG) box as a DNA-binding domain. WT1 encodes a transcription factor that contains four contiguous C2H2-type zinc-finger motifs as a DNA/RNA binding or protein-protein interaction domain. Here we report that WT1 binds to and acts synergistically with SRY to activate transcription from a promoter containing SRY-binding sites. This interaction is mediated by the WT1 zinc-finger domain and the SRY HMG box. WT1 mutants associated with Denys-Drash syndrome (DDS), which is characterized by Wilms' tumor, pseudohermaphroditism, and nephropathy, fail to interact with SRY. Wildtype WT1 is recruited to SRY-binding sites in an SRY-dependent manner, whereas DDS mutants are not recruited as efficiently. These results suggest that WT1 forms a complex with SRY to regulate transcription and that this WT1-SRY interaction is important in testis development.
肾母细胞瘤1（WT1）基因和Y染色体性别决定区（SRY）基因对哺乳动物性腺发育至关重要，这些基因的突变与人类性腺发育不全有关。SRY基因编码一种转录因子，其具有一个作为DNA结合结构域的高迁移率族（HMG）盒。WT1编码一种转录因子，其包含四个连续的C2H2型锌指基序作为DNA/RNA结合或蛋白质-蛋白质相互作用结构域。在此我们报告，WT1与SRY结合并协同作用，以激活来自含有SRY结合位点的启动子的转录。这种相互作用由WT1锌指结构域和SRY HMG盒介导。与以肾母细胞瘤、假两性畸形和肾病为特征的Denys-Drash综合征（DDS）相关的WT1突变体无法与SRY相互作用。野生型WT1以SRY依赖的方式被招募到SRY结合位点，而DDS突变体则不能被有效招募。这些结果表明，WT1与SRY形成复合物以调节转录，并且这种WT1-SRY相互作用在睾丸发育中很重要。
