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KMID : 0620920100420040294
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Experimental & Molecular Medicine
2010 Volume.42 No. 4 p.294 ~ p.301
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PKC-δ inhibitors sustain self-renewal of mouse embryonic stem cells under hypoxia in vitro
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Lee Hyo-Jong
Jeong Chul-Ho
Cha Jong-Ho
Kim Kyu-Won
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Abstract
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Under hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-1α (HIF-1α). Previous studies have demonstrated that PKC-δ is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-1α in human cancer cells. Furthermore, activation of PKC-δ mediates cardiac differentiation of ESCs and hematopoietic stem cells. However, the role of PKC-δ in hypoxia-induced early differentiation of mESCs remains largely unknown. Here, we show the inhibition of PKC-δ activity prevents the early differentiation of mESCs under hypoxia using PKC-δ inhibitors, GF 109203X and rottlerin. Reduction of PKC-δ activity under hypoxia effectively decreased HIF-1α protein levels and substantially recovered the expression of LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. Furthermore, PKC-δ 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-δ inhibitors block the early differentiation of mESCs via destabilization of HIF-1α under hypoxia.
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KEYWORD
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anoxia, embryonic stem cells, hypoxia-inducible factor 1, α subunit, protein kinase C-δ, rottlerin
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