PPARdelta agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/beta-catenin.
PPARdelta (peroxisome proliferator-activated receptor delta) is a member of the nuclear receptor superfamily. However, its function in tissues and cells is unknown, particularly as related to stem cell biology. We therefore investigated the PPARdelta effects on DNA synthesis in mouse embryonic stem cells (ES cells) and its related signal pathways. PPARdelta increased biphasic reactive oxygen species (ROS) production at 15 min and at 120 min incubation. PPARdelta significantly increased [(3)H] thymidine incorporation levels at various concentrations (10(-8) M to 10(-6) M) and incubation times (12 to 48 hr), and this activity was blocked by antioxidants. In addition, PPARdelta increased protein kinase C (PKC), cytosolic phospholipase A(2) (cPLA(2)) and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, and Wnt/beta-catenin activation. PPARdelta increased the protein levels of cell cycle regulators, and these levels were abolished by antioxidants, bisindolymaleimide I, SB203580 and beta-catenin specific siRNA. In addition, the effect of PPARdelta on increased [(3)H] thymidine incorporation was blocked by bisindolymaleimide I, SB203580 and beta-catenin specific siRNA. In conclusion, PPARdelta agonist enhanced mouse ES cells proliferation through ROS-mediated p38 MAPK and Wnt/beta-catenin activation.
Jeong
A Young
AY
Department of Veterinary Physiology, Biotherapy Human Resources Center (BK 21), College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
Lee
Min Young
MY
Lee
Sang Hun
SH
Park
Jae Hong
JH
Han
Ho Jae
HJ
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D051379:Mice; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010642:Phenoxyacetates / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D047494:PPAR delta; D010642:Phenoxyacetates; D017382:Reactive Oxygen Species; D051153:Wnt Proteins; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases; D054513:Group IV Phospholipases A2