Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Genes Cells. 2012 Sep;17(9):768-77. doi: 10.1111/j.1365-2443.2012.01626.x. Epub 2012 Aug 16.
Induced pluripotent stem cells (iPSCs) share many biological properties with embryonic stem cells (ESCs), and are generated from somatic cells by expression of some transcription factors such as Oct3/4, Sox2, Klf4 and c-Myc. Among these factors, the abundance of c-Myc is strictly regulated by Fbxw7, a subunit of Skp1-Cul1-F-box protein-type ubiquitin ligase. We have now shown that the expression of Fbxw7 was increased as ESCs differentiated. To investigate the role of Fbxw7 in the ESCs/iPSCs, we examined the impact of Fbxw7 ablation in the efficiency in iPSC generation. The frequency of iPSC generation from mouse embryonic fibroblasts (MEFs) lacking Fbxw7 was markedly greater than that from control MEFs. Depletion of Fbxw7 also resulted in promotion of iPSC generation. Morphology of iPSC clonies from Fbxw7-depleted MEFs appeared more undifferentiated than that from MEFs overexpressing c-Myc. Additional depletion of c-Myc did not abrogate the effect of Fbxw7 depletion, suggesting that c-Myc accumulation is not necessarily required for the increased efficiency in iPSC generation by Fbxw7 ablation. Substrates of Fbxw7 other than c-Myc might therefore play a key role in iPSC generation. These results suggest that transient inhibition of Fbxw7 would be a more promising approach to efficient generation of iPSCs than c-Myc over-expression.
诱导多能干细胞（iPSCs）与胚胎干细胞（ESCs）具有许多生物学特性，并且通过表达 Oct3/4、Sox2、Klf4 和 c-Myc 等转录因子从体细胞中产生。在这些因子中，c-Myc 的丰度受到 Fbxw7 的严格调节，Fbxw7 是 Skp1-Cul1-F-box 蛋白型泛素连接酶的一个亚基。我们现在已经表明，随着 ESCs 的分化，Fbxw7 的表达增加。为了研究 Fbxw7 在 ESCs/iPSCs 中的作用，我们检查了 Fbxw7 缺失对 iPSC 生成效率的影响。缺乏 Fbxw7 的小鼠胚胎成纤维细胞（MEFs）中 iPSC 的生成频率明显高于对照 MEFs。Fbxw7 的缺失也导致 iPSC 的生成增加。与过表达 c-Myc 的 MEFs 相比，来自 Fbxw7 缺失 MEFs 的 iPSC 克隆的形态似乎更未分化。进一步耗尽 c-Myc 并不能消除 Fbxw7 缺失的影响，这表明 c-Myc 的积累对于 Fbxw7 缺失导致的 iPSC 生成效率的提高并非必需。因此，Fbxw7 的除 c-Myc 以外的其他底物可能在 iPSC 生成中发挥关键作用。这些结果表明，与过表达 c-Myc 相比，Fbxw7 的短暂抑制可能是一种更有前途的高效生成 iPSC 的方法。
