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

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-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.

• Authors: Hyo-Jong Lee, Chul-Ho Jeong, Jong-Ho Cha, Kyu-Won Kim
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 42 Issue 4 Pg. 294-301 (Apr 30 2010) ISSN: 2092-6413 [Electronic] United States
• PMID: 20177147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Leukemia Inhibitory Factor Receptor alpha Subunit
• Lifr protein, mouse
• Protein Kinase Inhibitors
• STAT3 Transcription Factor
• Protein Kinase C

Topics

• Animals
• Cell Differentiation (drug effects)
• Cell Hypoxia (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Embryonic Stem Cells (cytology, drug effects, enzymology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Leukemia Inhibitory Factor Receptor alpha Subunit (metabolism)
• Mice
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• STAT3 Transcription Factor (metabolism)