PPARgamma regulates LIF-induced growth and self-renewal of mouse ES cells through Tyk2-Stat3 pathway.
Embryonic stem (ES) cells are genetically normal, pluripotent cells, capable of self-renewal and multi-lineage differentiation. Leukemia inhibitory factor (LIF) is a growth factor that can maintain the pluripotency of mouse ES cells in culture. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor transcription factors that regulate growth and differentiation of many cell types. We have shown earlier that 15-Deoxy-(12,14)-Prostaglandin J2 (15d-PGJ2), a natural ligand for PPARgamma, inhibits LIF-induced proliferation of mouse ES cells in culture. In this study we demonstrate that the PPARgamma antagonist Bisphenol A diglycidyl ether (BADGE) and 2-Chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907) reverse the inhibition of ES cell proliferation by PPARgamma agonists. Stable transfection of ES cells with a dominant negative PPARgamma1 mutant also reduced the inhibition of proliferation by PPARgamma agonists. While 15d-PGJ2 and ciglitazone-induced growth-arrest in ES cells by blocking LIF signaling, PPARgamma antagonists and dominant negative PPARgamma1 mutant reversed proliferation by restoring LIF-induced Tyk2-Stat3 signaling. These results suggest that PPARgamma regulates LIF-induced growth and self-renewal of mouse ES cells through Tyk2-Stat3 pathway.
Mo
Caiqing
C
Neuroscience Research Laboratory, Methodist Research Institute, Indianapolis, IN 46202, USA.
Chearwae
Wanida
W
Bright
John J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001559:Benzhydryl Compounds; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000378:metabolism*; D000098826:Bisphenol A Compounds
D000970:Antineoplastic Agents; D001549:Benzamides; D001559:Benzhydryl Compounds; D004852:Epoxy Compounds; D053605:Leukemia Inhibitory Factor; D047495:PPAR gamma; D015230:Prostaglandin D2; D011725:Pyridines; D050796:STAT3 Transcription Factor; D053634:TYK2 Kinase; C458508:T 0070907; C037112:9-deoxy-delta-9-prostaglandin D2; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds