Novel 5'TOPmRNAs regulated by ribosomal S6 kinase are important for cardiomyocyte development: S6 kinase suppression limits cardiac differentiation and promotes pluripotent cells toward a neural lineage.
Novel 5'TOPmRNAs regulated by ribosomal S6 kinase are important for cardiomyocyte development: S6 kinase suppression limits cardiac differentiation and promotes pluripotent cells toward a neural lineage.
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受核糖体 S6 激酶调节的新型 5TOPmRNA 对于心肌细胞发育非常重要：S6 激酶抑制限制心脏分化并促进多能细胞向神经谱系发展。
DOI：
10.1089/scd.2011.0582
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发表时间：
2012
影响因子：
4
通讯作者：
Gallicano,GIan
中科院分区：
文献类型：
--
作者：
Li,LeeAnn;Larabee,ShannonM;Chen,Shenglin;Basiri,Ladan;Yamaguchi,Seiji;Zakaria,Asif;Gallicano,GIan
将干细胞从实验室转移到临床一直是一项具有挑战性的任务。破坏这项任务的是理解和优化驱动干细胞分化为所需细胞和组织类型的潜在调节机制。在这里，我们提供的证据表明，核糖体S6激酶（S6K）是在胚胎干细胞（ESCs）和人类诱导多能干细胞分化为跳动的心肌细胞时上调的蛋白之一。我们假设S6K在心肌形成中起着关键作用，主要是因为它调节了最近显示具有5 ‘端寡聚嘧啶（5 ’ top）序列的3个与心脏相关的基因的翻译：连接蛋白43 （Cx43）、desmoplakin （Dsp）和磷酸酶和紧张素同源物（PTEN）。与另一个独立实验室一起，我们证实，与周围非跳动的分化细胞相比，S6K确实在跳动的esc来源的心肌细胞中上调。S6K短干扰rna转染的干细胞培养表明，抑制S6K强烈阻碍心肌细胞跳动的发展和Cx43、Dsp和PTEN的翻译；这些心脏5'TOP mrna仅在S6K细胞中正确翻译，支持我们的假设。一个意想不到的发现使S6K的作用更进一步：S6K敲低的干细胞培养比在典型的心脏分化方案下的胚状体中培养出更多的神经元。这些结果提出了一种新的观点，即除了其关键的心脏作用外，S6K可能是阻止干细胞追求神经元通路的重要因素。总的来说，结果表明S6K对于正常干细胞心肌形成的必要性，以及降低S6K表达对于干细胞神经发生的必要性。
Moving stem cells from bench to bedside has been a challenging task. Undermining this task is comprehending and optimizing the underlying regulatory mechanisms that drive differentiation of stem cells into desired cell and tissue types. Here we present evidence that ribosomal S6 kinase (S6K) is among the proteins upregulated as embryonic stem cells (ESCs) and human induced pluripotent stem cells differentiate into beating cardiomyocytes. We hypothesized that S6K plays a pivotal role in cardiomyogenesis, primarily because it regulates the translation of 3 cardiac-involved genes recently shown to have 5′ terminal oligopyrimidine (5′TOP) sequences: connexin 43 (Cx43), desmoplakin (Dsp), and phosphatase and tensin homolog (PTEN). Along with another independent laboratory, we confirmed that S6K is indeed upregulated in beating ESC-derived cardiomyocytes compared to the surrounding nonbeating, differentiated cells. S6K short interfering RNA-transfected stem cell cultures indicate that inhibition of S6K strongly hinders development of cardiomyocyte beating and translation of Cx43, Dsp, and PTEN; these cardiac 5′TOP mRNAs were only properly translated in cells with S6K, supporting our hypothesis. An unexpected discovery took the role of S6K one step further: S6K-knockdown stem cell cultures developed significantly more neurons than seen in embryoid bodies subjected to a typical cardiac differentiation protocol. These results introduced the novel idea that in addition to its critical cardiac roles, S6K may be a significant factor that prevents stem cells from pursuing a neuronal pathway. Overall, results have indicated the necessity of S6K for normal stem cell cardiomyogenesis, as well as lowered S6K expression for stem cell neurogenesis.