Wang Jianlong, Levasseur Dana N, Orkin Stuart H
Division of Hematology-Oncology, Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, and Howard Hughes Medical Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6326-31. doi: 10.1073/pnas.0802288105. Epub 2008 Apr 24.
Pluripotency of embryonic stem (ES) cells is maintained by transcription factors that form a highly interconnected protein interaction network surrounding the homeobox protein Nanog. Enforced expression of Nanog in mouse ES (mES) cells promotes self-renewal and alleviates their requirement for leukemia inhibitory factor (LIF). Understanding molecular mechanisms by which Nanog functions should illuminate fundamental properties of stem cells and the process of cellular reprogramming. Previously, we showed that Nanog forms multiple protein complexes in mES cells. Here, we demonstrate that Nanog dimerizes through its C-terminal domain rather than the homeodomain. Dimerization is required for interaction with other pluripotency network proteins. We also show that enforced expression of the Nanog dimer, but not the monomer, functionally replaces wild-type Nanog to sustain LIF-independent self-renewal of ES cells. Our results demonstrate that Nanog-Nanog homodimerization is a critical aspect of its function promoting stem cell pluripotency.
胚胎干细胞（ES细胞）的多能性由转录因子维持，这些转录因子围绕同源盒蛋白Nanog形成高度互联的蛋白质相互作用网络。在小鼠ES（mES）细胞中强制表达Nanog可促进自我更新，并减轻它们对白血病抑制因子（LIF）的需求。了解Nanog发挥功能的分子机制应能阐明干细胞的基本特性以及细胞重编程过程。此前，我们表明Nanog在mES细胞中形成多种蛋白质复合物。在此，我们证明Nanog通过其C端结构域而非同源结构域二聚化。二聚化是与其他多能性网络蛋白相互作用所必需的。我们还表明，强制表达Nanog二聚体而非单体，在功能上可替代野生型Nanog以维持ES细胞不依赖LIF的自我更新。我们的结果表明，Nanog-Nanog同源二聚化是其促进干细胞多能性功能的关键方面。
