Involvement of GSK-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolylmaleimides.
The ability to propagate embryonic stem cells (ESCs) while maintaining their pluripotency is critical if their potential use in regenerative medicine is to be realized. The mechanisms controlling ESC self-renewal are under intense investigation, and glycogen synthase kinase 3 (GSK-3) has been implicated in regulating both self-renewal and differentiation. To clarify its role in ESCs we have used chemical genetics. We synthesized a series of bisindolylmaleimides, a subset of which inhibit GSK-3 in murine ESCs and robustly enhance self-renewal in the presence of leukemia inhibitory factor (LIF) and serum, but not in the absence of LIF. Importantly, these molecules appear selective for GSK-3 and do not perturb other signaling pathways regulating self-renewal. Our study clarifies the functional importance of GSK-3 in regulation of ESC self-renewal and provides tools for investigating its role further.
Bone
Heather K
HK
Department of Pharmacy and Pharmacology, Centre for Regenerative Medicine, University of Bath, Bath, UK.
Damiano
Teresa
T
Bartlett
Stephen
S
Perry
Alexis
A
Letchford
Julie
J
Ripoll
Yolanda Sanchez
YS
Nelson
Adam S
AS
Welham
Melanie J
MJ
D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice
D007211:Indoles; D053605:Leukemia Inhibitory Factor; D008301:Maleimides; D038362:Glycogen Synthase Kinase 3; C088060:bisindolylmaleimide