5-Aminoimidazole-4-carboxyamide ribonucleoside induces G(1)/S arrest and Nanog downregulation via p53 and enhances erythroid differentiation.
5-Aminoimidazole-4-carboxyamide ribonucleoside induces G(1)/S arrest and Nanog downregulation via p53 and enhances erythroid differentiation.
复制标题
DOI：
10.1002/stem.778
复制
发表时间：
2012-02
期刊：
影响因子：
5.2
通讯作者：
Broxmeyer, Hal E.
中科院分区：
文献类型：
--
作者：
Chae, Hee-Don;Lee, Man-Ryul;Broxmeyer, Hal E.
能量代谢如何影响胚胎干细胞（ES）多能性的分子机制仍不清楚。腺苷酸活化蛋白激酶（AMPK）是控制能量代谢的关键调节因子，在ATP耗竭应激时被激活。我们通过利用5-氨基咪唑-4-羧酰胺核糖核苷（AICAR）作为AMPK的激活剂来研究细胞能量稳态是否与小鼠（m）ES细胞的自我更新和多能性的维持相关。我们证明AICAR处理激活p53/p21通路，并通过诱导G1/S期细胞周期阻滞显著抑制R1 mES细胞的增殖，而不影响凋亡。在LIF存在的情况下，AICAR治疗还显著降低了多能干细胞标志物Nanog和SSEA-1，而不影响Oct 4的表达。H9人（h）ES细胞也通过诱导p53活化和抑制Nanog表达对AICAR作出响应。AICAR瞬时降低mES细胞中Nanog mRNA水平，这种作用不是由于可抑制Nanog表达的miR-134的表达。AICAR诱导Nanog降解，这一作用可被蛋白酶体抑制剂MG 132抑制。虽然AICAR减少了mES细胞的胚状体（EB）形成，但它增加了红系细胞谱系标志物（Ter 119、GATA 1、Klf 1、Hbb-b和Hbb-bh 1）的表达水平。虽然AICAR增强了红系分化，但AICAR处理的细胞中内皮细胞谱系群体显著减少。我们的研究结果表明，AMPK活性调节的能量代谢可能控制的自我更新和分化的ES细胞的平衡。
Molecular mechanisms of how energy metabolism affects embryonic stem (ES) cell pluripotency remain unclear. AMP-activated protein kinase (AMPK), a key regulator for controlling energy metabolism, is activated in response to ATP-exhausting stress. We investigated whether cellular energy homeostasis is associated with maintenance of self-renewal and pluripotency in mouse (m) ES cells by utilizing 5-Aminoimidazole-4-carboxyamide ribonucleoside (AICAR) as an activator of AMPK. We demonstrate that AICAR treatment activates the p53/p21 pathway, and markedly inhibits proliferation of R1 mES cells by inducing G1/S phase cell cycle arrest, without influencing apoptosis. Treatment with AICAR also significantly reduces pluripotent stem cell markers, Nanog and SSEA-1, in the presence of LIF, without affecting expression of Oct4. H9 human (h) ES cells also responded to AICAR with induction of p53 activation and repression of Nanog expression. AICAR reduced Nanog mRNA levels in mES cells transiently, an effect not due to expression of miR-134 which can suppress Nanog expression. AICAR induced Nanog degradation, an effect inhibited by MG132, a proteasome-inhibitor. Although AICAR reduced embryoid body (EB) formation from mES cells, it increased expression levels of erythroid cell lineage markers (Ter119, GATA1, Klf1, Hbb-b and Hbb-bh1). While erythroid differentiation was enhanced by AICAR, endothelial lineage populations were remarkably reduced in AICAR-treated cells. Our results suggest that energy metabolism regulated by AMPK activity may control the balance of self-renewal and differentiation of ES cells.
登录
查看更多内容
影响因子：
11.8
作者：
Dasgupta, Biplab;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey
影响因子：
14.8
作者：
Bracha, Abigail L.;Ramanathan, Arvind;Huang, Sui;Ingber, Donald E.;Schreiber, Stuart L.
通讯作者：
Schreiber, Stuart L.
影响因子：
5.6
作者：
Kasai, Takayuki;Bandow, Kenjiro;Matsuguchi, Tetsuya
通讯作者：
Matsuguchi, Tetsuya
影响因子：
4
作者：
Chae, Hee-Don;Broxmeyer, Hal E.
通讯作者：
Broxmeyer, Hal E.
影响因子：
16
作者：
Jones, RG;Plas, DR;Thompson, CB
通讯作者：
Thompson, CB