Reciprocal regulation of Akt and Oct4 promotes the self-renewal and survival of embryonal carcinoma cells.
Reciprocal regulation of Akt and Oct4 promotes the self-renewal and survival of embryonal carcinoma cells.
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DOI：
10.1016/j.molcel.2012.08.030
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发表时间：
2012-11-30
期刊：
影响因子：
16
通讯作者：
Wang, Ying-Jie
中科院分区：
文献类型：
--
作者：
Lin, Yuanji;Yang, Ying;Li, Weihua;Chen, Qi;Li, Jie;Pan, Xiao;Zhou, Lina;Liu, Changwei;Chen, Chunsong;He, Jianqin;Cao, Hongcui;Yao, Hangping;Zheng, Li;Xu, Xiaowei;Xia, Zongping;Ren, Jiangtao;Xiao, Lei;Li, Lanjuan;Shen, Binghui;Zhou, Honglin;Wang, Ying-Jie
通过Akt丝氨酸/苏氨酸蛋白激酶的信号传导在胚胎干细胞及其恶性对应物胚胎癌细胞（ECCs）的自我更新中起关键作用。在这里，我们表明，在ECCs中，Akt在苏氨酸235处磷酸化主要多能性因子Oct 4，并且ECCs中磷酸化Oct 4的水平与细胞凋亡抗性和致瘤潜力相关。Oct 4的磷酸化增加了其稳定性，并促进了其核定位及其与Sox 2的相互作用，从而促进了核心干基因POU 5 F1和NANOG的转录。此外，在ECCs中，未磷酸化的Oct 4与AKT 1启动子结合并抑制其转录。Akt对Oct 4的磷酸化导致Oct 4从AKT 1启动子上解离，这激活了AKT 1转录并促进了细胞存活。因此，Oct 4蛋白的位点特异性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。
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, post-translational 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.
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影响因子：
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