PKC-delta inhibitors sustain self-renewal of mouse embryonic stem cells under hypoxia in vitro.
PKC-delta inhibitors sustain self-renewal of mouse embryonic stem cells under hypoxia in vitro.
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PKC-δ 抑制剂在体外缺氧条件下维持小鼠胚胎干细胞的自我更新。
DOI：
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发表时间：
2010
影响因子：
12.8
通讯作者：
Kyu
中科院分区：
文献类型：
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作者：
Hyo;C. Jeong;Jong;Kyu
在缺氧条件下，小鼠胚胎干细胞（mESC）失去自我更新活性，并显示由缺氧诱导因子-1 α（HIF-1 α）介导的早期分化形态。以前的研究表明，PKC-δ被缺氧激活，并增加了人类癌细胞中HIF-1 α的蛋白质稳定性和转录活性。此外，PKC-δ的活化介导ESC和造血干细胞的心脏分化。然而，PKC-δ在缺氧诱导的mESCs早期分化中的作用仍然很大程度上未知。在这里，我们显示了PKC-δ活性的抑制防止了缺氧条件下使用PKC-δ抑制剂GF 109203 X和rottlerin的mESC的早期分化。低氧条件下PKC-δ活性的降低有效地降低了HIF-1 α蛋白水平，并基本上恢复了mESC中LIF特异性受体（LIFR）和磷酸化STAT 3的表达。此外，PKC-δ抑制剂有助于维持自我更新标志物的表达，并抑制缺氧条件下mESC中早期分化标志物的表达。总之，这些结果表明，PKC-δ抑制剂通过缺氧条件下HIF-1 α的不稳定性阻断mESC的早期分化。
Under hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-1 alpha (HIF-1 alpha). Previous studies have demonstrated that PKC-delta is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-1 alpha in human cancer cells. Furthermore, activation of PKC-delta mediates cardiac differentiation of ESCs and hematopoietic stem cells. However, the role of PKC-delta in hypoxia-induced early differentiation of mESCs remains largely unknown. Here, we show the inhibition of PKC-delta activity prevents the early differentiation of mESCs under hypoxia using PKC-delta inhibitors, GF 109203X and rottlerin. Reduction of PKC-delta activity under hypoxia effectively decreased HIF-1 alpha protein levels and substantially recovered the expression of LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. Furthermore, PKC-delta inhibitors aid to sustain the expression of self-renewal markers and suppress the expression of early differentiation markers in mESCs under hypoxia. Taken together, these results suggest that PKC-delta inhibitors block the early differentiation of mESCs via destabilization of HIF-1 alpha under hypoxia.