title: Involvement of GSK-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolylmaleimides.
abstract: 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.
authors.affiliation: Department of Pharmacy and Pharmacology, Centre for Regenerative Medicine, University of Bath, Bath, UK.
authors.forename: Heather K
authors.initials: HK
authors.lastname: Bone
authors.forename: Teresa
authors.initials: T
authors.lastname: Damiano
authors.forename: Stephen
authors.initials: S
authors.lastname: Bartlett
authors.forename: Alexis
authors.initials: A
authors.lastname: Perry
authors.forename: Julie
authors.initials: J
authors.lastname: Letchford
authors.forename: Yolanda Sanchez
authors.initials: YS
authors.lastname: Ripoll
authors.forename: Adam S
authors.initials: AS
authors.lastname: Nelson
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Welham
mesh_terms: 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
chemical_list: D007211:Indoles; D053605:Leukemia Inhibitory Factor; D008301:Maleimides; D038362:Glycogen Synthase Kinase 3; C088060:bisindolylmaleimide