title: Glycogen synthase kinase-3beta regulates differentiation-induced apoptosis of human neural progenitor cells.
abstract: Glycogen synthase kinase-3beta is a multifunctional key regulator enzyme in neural developmental processes and a main component of the canonical Wnt signaling pathway. It is already known that the Wnt-driven differentiation of neural progenitor cells is accompanied by an increase of apoptosis at which the pro-apoptotic function of GSK-3beta is still discussed. The aim of the present study was to investigate whether the phosphorylation level of GSK-3beta at serine 9 is the primary regulatory mechanism of differentiation-induced apoptosis. Differentiating human neural ReNcell VM progenitor cells were treated with the specific GSK-3beta inhibitor SB216763 (10 μM) and analyzed in respect to the intrinsic apoptosis pathway regulation using microscopy and protein expression analysis. Differentiation of ReNcell VM cells was accompanied by cell morphological changes, cytoskeleton rearrangement and apoptosis increase. Treatment of differentiating cells with SB216763 induced a significant dephosphorylation of GSK-3beta at serine 9 accompanied by a significant decrease of apoptosis of about 0.7±0.03% and reduced activation of caspase-3 as well as BAX and PARP cleavage during the first 12h of differentiation compared to untreated, differentiating cells. Dephosphorylation of GSK-3beta at serine 9 appears not solely to be responsible for its pro-apoptotic function, because we observed a decrease of intrinsic apoptosis after treatment of the cells with the specific GSK-3beta inhibitor SB216763. We assume that GSK-3beta drives neural progenitor cell apoptosis by direct interaction with pro-apoptotic BAX or by indirect influence on the canonical Wnt/beta-catenin target gene transcription.
authors.affiliation: University of Rostock, Institute of Biological Sciences, Cell Biology and Biosystems Technology, Albert-Einstein-Straße 3, D-18051 Rostock, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Jaeger
authors.forename: Jana
authors.initials: J
authors.lastname: Baake
authors.forename: Dieter G
authors.initials: DG
authors.lastname: Weiss
authors.forename: Ralf
authors.initials: R
authors.lastname: Kriehuber
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D015800:Protozoan Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; C417521:SB 216763; D014404:Tubulin; D051028:bcl-2-Associated X Protein; C053277:procyclic acidic repetitive protein, Trypanosoma; D012694:Serine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3