Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
EMBO J. 2012 Jan 4;31(1):83-94. doi: 10.1038/emboj.2011.360. Epub 2011 Sep 30.
Various cellular stresses including oxidative stress induce a collapse of the Ran gradient, which causes accumulation of importin α in the nucleus and a subsequent block of nuclear protein import. However, it is unknown whether accumulated importin α performs roles in the nucleus after its migration in response to stress. In this study, we found that nuclear-retained importin α2 binds with DNase I-sensitive nuclear component(s) and exhibits selective upregulation of mRNA encoding Serine/threonine kinase 35 (STK35) by microarray analysis. Chromatin immunoprecipitation and promoter analysis demonstrated that importin α2 can access to the promoter region of STK35 and accelerate its transcription in response to hydrogen peroxide exposure. Furthermore, constitutive overexpression of STK35 proteins enhances caspase-independent cell death under oxidative stress conditions. These results collectively reveal that nuclear-localized importin α2 influences gene expression and contributes directly to cell fate outcomes including non-apoptotic cell death.
各种细胞应激，包括氧化应激，会导致 Ran 梯度崩溃，这会导致导入蛋白α在核内积累，并随后阻止核蛋白导入。然而，尚不清楚在应激反应中导入蛋白α迁移后，其在核内是否发挥作用。在这项研究中，我们发现核内滞留的导入蛋白α2与 DNA 酶 I 敏感的核成分结合，并通过微阵列分析显示选择性地上调编码丝氨酸/苏氨酸激酶 35（STK35）的 mRNA。染色质免疫沉淀和启动子分析表明，导入蛋白α2可以进入 STK35 的启动子区域，并在暴露于过氧化氢时加速其转录。此外，STK35 蛋白的组成性过表达增强了氧化应激条件下的 caspase 非依赖性细胞死亡。这些结果共同表明，核内定位的导入蛋白α2会影响基因表达，并直接影响包括非凋亡性细胞死亡在内的细胞命运结局。
