Exp Mol Med.  2010 Apr;42(4):294-301. 10.3858/emm.2010.42.4.028.

PKC-delta inhibitors sustain self-renewal of mouse embryonic stem cells under hypoxia in vitro

Affiliations
  • 1Research Institute of Pharmaceutical Sciences, NeuroVascular Coordination Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea. qwonkim@plaza.snu.ac.kr
  • 2The Hormel Institute, University of Minnesota 801, 16th AVE, NE, Austin, MN55912, USA.
  • 3Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, Korea.

Abstract

Under hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-1alpha (HIF-1alpha). Previous studies have demonstrated that PKC-delta is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-1alpha 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-1alpha 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-1alpha under hypoxia.

Keyword

anoxia; embryonic stem cells; hypoxia-inducible factor 1, alpha subunit; protein kinase C-delta; rottlerin
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