Carlson Bradley A, Schweizer Ulrich, Perella Christine, Shrimali Rajeev K, Feigenbaum Lionel, Shen Liya, Speransky Svetlana, Floss Thomas, Jeong Soon-Jeong, Watts Jennifer, Hoffmann Victoria, Combs Gerald F, Gladyshev Vadim N, Hatfield Dolph L
Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, NCI (National Cancer Institute), NIH (National Institutes of Health), Bethesda, MD 20892, USA.
Biochem J. 2009 Feb 15;418(1):61-71. doi: 10.1042/BJ20081304.
STAF [Sec (selenocysteine) tRNA gene transcription activating factor] is a transcription activating factor for a number of RNA Pol III- and RNA Pol II-dependent genes including the Trsp [Sec tRNA gene], which in turn controls the expression of all selenoproteins. Here, the role of STAF in regulating expression of Sec tRNA and selenoproteins was examined. We generated transgenic mice expressing the Trsp transgene lacking the STAF-binding site and made these mice dependent on the transgene for survival by removing the wild-type Trsp. The level of Sec tRNA was unaffected or slightly elevated in heart and testis, but reduced approximately 60% in liver and kidney, approximately 70% in lung and spleen and approximately 80% in brain and muscle compared with the corresponding organs in control mice. Moreover, the ratio of the two isoforms of Sec tRNA that differ by methylation at position 34 (Um34) was altered significantly, and the Um34-containing form was substantially reduced in all tissues examined. Selenoprotein expression in these animals was most affected in tissues in which the Sec tRNA levels were most severely reduced. Importantly, mice had a neurological phenotype strikingly similar to that of mice in which the selenoprotein P gene had been removed and their life span was substantially reduced. The results indicate that STAF influences selenoprotein expression by enhancing Trsp synthesis in an organ-specific manner and by controlling Sec tRNA modification in each tissue examined.
STAF[硒代半胱氨酸（Sec）tRNA基因转录激活因子]是多种RNA聚合酶III和RNA聚合酶II依赖性基因的转录激活因子，包括Trsp[Sec tRNA基因]，而Trsp又控制着所有硒蛋白的表达。在此，研究了STAF在调节Sec tRNA和硒蛋白表达中的作用。我们构建了表达缺失STAF结合位点的Trsp转基因的转基因小鼠，并通过去除野生型Trsp使这些小鼠依赖转基因存活。与对照小鼠的相应器官相比，Sec tRNA水平在心脏和睾丸中未受影响或略有升高，但在肝脏和肾脏中降低了约60%，在肺和脾脏中降低了约70%，在脑和肌肉中降低了约80%。此外，在34位（Um34）甲基化不同的两种Sec tRNA同工型的比例发生了显著改变，并且在所检查的所有组织中，含Um34的形式大幅减少。这些动物中的硒蛋白表达在Sec tRNA水平降低最严重的组织中受影响最大。重要的是，小鼠具有与硒蛋白P基因被敲除的小鼠极为相似的神经学表型且其寿命大幅缩短。结果表明，STAF通过以器官特异性方式增强Trsp合成以及控制所检查的每个组织中的Sec tRNA修饰来影响硒蛋白表达。
