Department of Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Dev Cell. 2013 Jul 29;26(2):123-35. doi: 10.1016/j.devcel.2013.06.022.
We recently demonstrated that the expression of the importin α subtype is switched from α2 to α1 during neural differentiation in mouse embryonic stem cells (ESCs) and that this switching has a major impact on cell differentiation. In this study, we report a cell-fate determination mechanism in which importin α2 negatively regulates the nuclear import of certain transcription factors to maintain ESC properties. The nuclear import of Oct6 and Brn2 was inhibited via the formation of a transport-incompetent complex of the cargo bound to a nuclear localization signal binding site in importin α2. Unless this dominant-negative effect was downregulated upon ESC differentiation, inappropriate cell death was induced. We propose that although certain transcription factors are necessary for differentiation in ESCs, these factors are retained in the cytoplasm by importin α2, thereby preventing transcription factor activity in the nucleus until the cells undergo differentiation.
我们最近证明，在小鼠胚胎干细胞（ESCs）的神经分化过程中，输入蛋白 α 亚基的表达从 α2 切换到 α1，这种切换对细胞分化有重大影响。在这项研究中，我们报告了一种细胞命运决定机制，其中输入蛋白 α2 负调控某些转录因子的核输入，以维持 ESC 特性。Oct6 和 Brn2 的核输入通过与输入蛋白 α2 中的核定位信号结合位点结合的货物形成运输无能力的复合物而被抑制。除非在 ESC 分化时下调这种显性负效应，否则会诱导细胞死亡。我们提出，尽管某些转录因子对于 ESCs 的分化是必需的，但这些因子被输入蛋白 α2 保留在细胞质中，从而阻止转录因子在细胞核中的活性，直到细胞发生分化。
