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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice
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Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice

机译：类固醇受体共激活因子（SRC）-1和转录中介因子（TIF）2在小鼠雄激素受体活性中的作用

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摘要

Genetic disruption of the steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)2/SRC-2 in mouse resulted in distinctive mutant phenotypes. To quantify their roles in the function of androgen receptor (AR) transcriptional activity in vivo, we generated a unique transgenic AR-reporter mouse and analyzed the cell-specific contributions of SRC-11 and TIF2 to the activity of AR in mouse testis. Transgenic AR-luciferase and transgenic AR-lacZ mice harbor a recombinant mouse AIR gene, AR(GAL4DBD), which is functionally coupled with a upstream activation sequence-mediated reporter gene (AR activity indicator). After characterization of these mice in terms of AIR function, we further derived bigenic mice by crossing AIR activity indicator mice with the SRC-1(-/-) or TIF2(+/-) mutant mice. Analyses of the resultant bigenic mice by in vivo imaging and luciferase assays showed that testicular AIR activity was decreased significantly in those with the TIF2(+/-) mutation but not in the SRC-1(+/-) background, suggesting that TIF2 serves as the preferential coactivator for AIR in testis. Immunohistological analysis confirmed that AIR and TIF2 coexist in mouse testicular Sertoli cell nuclei under normal conditions. Although SRC-1 concentrates in Sertoli cell nuclei in the absence of TIF2, nuclear SRC-11 is not able to rescue AIR activity in the TIF2 mutant background. Interestingly, SRC-11 appears to negatively influence AIR activity, thereby counterbalancing the TIF2-stimulated AIR activity. Our results provide unique in vivo insights to the multidimensional cell-type-specific interactions between AIR and coregulators.
机译：小鼠中类固醇受体共激活因子（SRC）-1和转录中间因子（TIF）2 / SRC-2的遗传破坏导致独特的突变表型。为了量化其在体内雄激素受体（AR）转录活性功能中的作用，我们生成了独特的转基因AR-reporter小鼠，并分析了SRC-11和TIF2对小鼠睾丸中AR活性的细胞特异性贡献。转基因AR-荧光素酶和转基因AR-lacZ小鼠具有重组小鼠AIR基因AR（GAL4DBD），该基因与上游激活序列介导的报告基因（AR活性指示剂）功能性偶联。在根据AIR功能对这些小鼠进行表征后，我们通过将AIR活性指示剂小鼠与SRC-1（-/-）或TIF2（+/-）突变小鼠杂交，进一步衍生了双基因小鼠。通过体内成像和荧光素酶分析对生成的双基因小鼠的分析表明，在那些具有TIF2（+/-）突变的动物中，睾丸AIR活性显着降低，而在SRC-1（+/-）背景中则没有，这表明TIF2具有作为睾丸中AIR的优先激活剂。免疫组织学分析证实，正常情况下，小鼠睾丸支持细胞的细胞核中AIR和TIF2共存。尽管在没有TIF2的情况下SRC-1集中在支持细胞的细胞核中，但核SRC-11不能在TIF2突变体背景下拯救AIR活性。有趣的是，SRC-11似乎会对AIR活动产生负面影响，从而平衡了TIF2刺激的AIR活动。我们的结果为AIR和成核剂之间多维细胞类型特异性相互作用提供了独特的体内见解。

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