State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310003, China.
Mol Cell. 2012 Nov 30;48(4):627-40. doi: 10.1016/j.molcel.2012.08.030. Epub 2012 Oct 4.
Signaling via the Akt serine/threonine protein kinase plays critical roles in the self-renewal of embryonic stem cells and their malignant counterpart, embryonal carcinoma cells (ECCs). Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. Phosphorylation of Oct4 by Akt resulted in dissociation of Oct4 from the AKT1 promoter, which activated AKT1 transcription and promoted cell survival. Therefore, a site-specific, posttranslational modification of the Oct4 protein orchestrates the regulation of its stability, subcellular localization, and transcriptional activities, which collectively promotes the survival and tumorigenicity of ECCs.
Akt 丝氨酸/苏氨酸蛋白激酶的信号转导在胚胎干细胞及其恶性对应物胚胎癌细胞（ECCs）的自我更新中发挥着关键作用。在这里，我们表明在 ECCs 中，Akt 将主多能性因子 Oct4 磷酸化丝氨酸 235 位，并且 ECCs 中磷酸化 Oct4 的水平与抗凋亡和致瘤潜能相关。Oct4 的磷酸化增加了其稳定性，并促进了其核定位及其与 Sox2 的相互作用，从而促进了核心干性基因 POU5F1 和 NANOG 的转录。此外，在 ECCs 中，未磷酸化的 Oct4 与 AKT1 启动子结合并抑制其转录。Akt 对 Oct4 的磷酸化导致 Oct4 从 AKT1 启动子解离，从而激活 AKT1 转录并促进细胞存活。因此，Oct4 蛋白的特定翻译后修饰协调了其稳定性、亚细胞定位和转录活性的调节，这共同促进了 ECCs 的存活和致瘤性。
