Regulation of embryonic stem cell pluripotency by heat shock protein 90.
Regulation of embryonic stem cell pluripotency by heat shock protein 90.
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DOI：
10.1002/stem.1143
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发表时间：
2012-08
期刊：
影响因子：
5.2
通讯作者：
Wang, Guanghu
中科院分区：
文献类型：
--
作者：
Bradley, Eric;Bieberich, Erhard;Mivechi, Nahid F.;Tangpisuthipongsa, Dantera;Wang, Guanghu
破译干细胞多能性的分子基础对于理解干细胞生物学、早期胚胎发育和再生医学的临床应用是至关重要的。分子伴侣热休克蛋白90（Hsp 90）通过调节多种多能性因子（Oct 4、Nanog和信号转导和转录激活因子3（Stat 3））对小鼠胚胎干细胞（ESC）的多能性起重要作用。通过17-N-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）或miRNA抑制Hsp 90导致ESC分化。Hsp 90 β的过表达部分挽救了表型;特别是，Oct 4和Nanog的水平恢复。值得注意的是，Hsp 90与Oct 4和Nanog在相同的细胞复合物中结合，并保护它们免受泛素蛋白酶体途径的降解，这表明Oct 4和Nanog是潜在的新型Hsp 90客户蛋白。此外，Hsp 90抑制降低Oct 4的mRNA水平，但不降低Nanog的mRNA水平，表明Hsp 90参与Oct 4 mRNA加工或成熟。Hsp 90抑制也增加了中胚层谱系的一些蛋白质标记物的表达，这意味着Hsp 90抑制了ESC的中胚层分化。这些发现支持了Hsp 90通过维持多种多能性因子（特别是Oct 4和Nanog）的水平来维持ESC多能性的新作用。
Deciphering the molecular basis of stem cell pluripotency is fundamental to the understanding of stem cell biology, early embryonic development, and to the clinical application of regenerative medicine. We report here that the molecular chaperone heat shock protein 90 (Hsp90) is essential for mouse embryonic stem cell (ESC) pluripotency through regulating multiple pluripotency factors, including Oct4, Nanog and signal transducer and activator of transcription 3 (Stat3). Inhibition of Hsp90 by either 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) or miRNA led to ESC differentiation. Over-expression of Hsp90β partially rescued the phenotype; in particular, the levels of Oct4 and Nanog were restored. Notably, Hsp90 associated with Oct4 and Nanog in the same cellular complex and protected them from degradation by the ubiquitin proteasome pathway, suggesting that Oct4 and Nanog are potential novel Hsp90 client proteins. In addition, Hsp90 inhibition reduced the mRNA level of Oct4, but not that of Nanog, indicating Hsp90 participates in Oct4 mRNA processing or maturation. Hsp90 inhibition also increased expression of some protein markers for mesodermal lineages, implying that Hsp90 suppresses mesodermal differentiation from ESCs. These findings support a new role for Hsp90 in maintaining ESC pluripotency by sustaining the level of multiple pluripotency factors, particularly Oct4 and Nanog.
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影响因子：
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