Proapoptotic Stimuli Induce Nuclear Accumulation of Glycogen Synthase Kinase-3β

Abstract

The goal of this study was to determine whether the intracellular distribution of the proapoptotic enzyme glycogen synthase kinase-3β (GSK-3β) is dynamically regulated by conditions that activate apoptotic signaling cascades. In untreated human neuroblastoma SH-SY5Y cells, GSK-3β was predominantly cytosolic, although a low level was also detected in the nucleus. The nuclear level of GSK-3β was rapidly increased after exposure of cells to serum-free media, heat shock, or staurosporine. Although each of these conditions caused changes in the serine 9 and/or tyrosine phosphorylation of GSK-3β, neither of these modifications was correlated with nuclear accumulation of GSK-3β. Heat shock and staurosporine treatments increased nuclear GSK-3β prior to activation of caspase-9 and caspase-3, and this nuclear accumulation of GSK-3β was unaltered by pretreatment with a general caspase inhibitor. The GSK-3β inhibitor lithium did not alter heat shock-induced nuclear accumulation of GSK-3β but increased the nuclear level of cyclin D1, indicating that cyclin D1 is a substrate of nuclear GSK-3β. Thus, the intracellular distribution of GSK-3β is dynamically regulated by signaling cascades, and apoptotic stimuli cause increased nuclear levels of GSK-3β, which facilitates interactions with nuclear substrates.