Pan Xiao, Cang Xiaohui, Dan Songsong, Li Jingchao, Cheng Jie, Kang Bo, Duan Xiaotao, Shen Binghui, Wang Ying-Jie
From the College of Life Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310003, China.
J Biol Chem. 2016 Aug 26;291(35):18353-69. doi: 10.1074/jbc.M116.745414. Epub 2016 Jul 1.
Although the Oct4/Sox2 complex is crucial for maintaining the pluripotency of stem cells, the molecular basis underlying its regulation during lineage-specific differentiation remains unknown. Here, we revealed that the highly conserved Oct4/Lys-156 is important for maintaining the stability of the Oct4 protein and the intermolecular salt bridge between Oct4/Lys-151 and Sox2/Asp-107 that contributes to the Oct4/Sox2 interaction. Post-translational modifications at Lys-156 and K156N, a somatic mutation detected in bladder cancer patients, both impaired the Lys-151-Asp-107 salt bridge and the Oct4/Sox2 interaction. When produced as a recombinant protein or overexpressed in pluripotent stem cells, Oct4/K156N, with reduced binding to Sox2, significantly down-regulated the stemness genes that are cooperatively controlled by the Oct4/Sox2 complex and specifically up-regulated the mesendodermal genes and the SNAIL family genes that promote the epithelial-mesenchymal transition. Thus, we conclude that Oct4/Lys-156-modulated Oct4/Sox2 interaction coordinately controls the epithelial-mesenchymal transition and mesendoderm specification induced by specific differentiation signals.
尽管Oct4/Sox2复合物对于维持干细胞的多能性至关重要，但其在谱系特异性分化过程中调控的分子基础仍不清楚。在此，我们揭示了高度保守的Oct4/Lys-156对于维持Oct4蛋白的稳定性以及Oct4/Lys-151与Sox2/Asp-107之间有助于Oct4/Sox2相互作用的分子间盐桥很重要。Lys-156的翻译后修饰以及在膀胱癌患者中检测到的体细胞突变K156N，均损害了Lys-151-Asp-107盐桥和Oct4/Sox2相互作用。当作为重组蛋白产生或在多能干细胞中过表达时，与Sox2结合减少的Oct4/K156N显著下调了由Oct4/Sox2复合物协同控制的干性基因，并特异性上调了促进上皮-间质转化的中胚层基因和SNAIL家族基因。因此，我们得出结论，Oct4/Lys-156调节的Oct4/Sox2相互作用协同控制由特定分化信号诱导的上皮-间质转化和中胚层内胚层特化。
