Glycogen Synthase Kinase-3 Plays a Central Role in Mediating Glucocorticoid-Induced Apoptosis

Abstract

It is still unclear how glucocorticoids (GCs) induce apoptosis of thymocytes and T lymphoma cells. Emergence of GC-resistant lymphoma cells is a major obstacle in GC therapy, emphasizing the need for novel strategies that maintain the sensitivity of lymphoma cells to the proapoptotic effects of GC. We have undertaken a kinome study to elucidate the signal transduction pathways involved in mediating GC-induced apoptosis. Our study shows that glycogen synthase kinase (GSK3) plays a central role in promoting GC-induced apoptosis. In the absence of a ligand, GSK3alpha, but not GSK3beta, is sequestered to the glucocorticoid receptor (GR). Exposure to GCs leads to dissociation of GSK3alpha from GR and subsequent interaction of GSK3alpha and GSK3beta with the proapoptotic Bim protein, an essential mediator of GC-induced apoptosis. Chemical inhibition of GSK3 by SB216763, BIO-Acetoxime, or LiCl and GSK3 inhibition using a dominant-negative mutant of GSK3 impede this cell death process, indicating that GSK3 is involved in transmitting the apoptotic signal. GC resistance in lymphoma cells can be relieved by inhibiting the phosphatidylinositol-3 kinase-Akt survival pathway, which inactivates GSK3. Notch1, a transcription factor frequently activated in T acute lymphoblastic leukemia cells, confers GC resistance through activation of Akt. Altogether, this study illuminates the link connecting upstream GR signals to the downstream mediators of GC-induced apoptosis. Our data suggest that targeting protein kinases involved in GSK3 inactivation should improve the outcome of GC therapy.

Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication

“…18BIOder is a cytoprotective small-molecule inhibitor. GSK-3␤ inhibitors have been shown to have prosurvival activity and to regulate cell proliferation in various cell types (96)(97)(98)(99). In order to exclude potential cytotoxicity of our compounds, we first assessed the effects of 18BIOder on cell viability in various cell lines, including uninfected (CEM and Jurkat) and HIV-1-infected T cells (ACH2 and J1.1) and monocytes (U937 and HIV-1-infected U1).…”

PI3K/mTOR Inhibition Markedly Potentiates HDAC Inhibitor Activity in NHL Cells through BIM- and MCL-1–Dependent Mechanisms In Vitro and In Vivo

“…Moreover the findings that GSK3 inhibitors BIO or CHIR-98014 significantly diminished BEZ235/panobinostat lethality argue for a functional role for GSK3 in cell death mediated by this regimen. GSK3 pro-apoptotic activity involves multiple mechanisms, including perturbations in Mcl-1, Bim, FOXO3, β-catenin, c-Myc, and Cyclin D1 among others [42, 43]. However, the mechanism(s) involved in the present studies remains to be determined.…”

Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland

“…21) and phosphorylates different steroid receptors including estrogen receptor ␣ (22), glucocorticoid receptor (23), and androgen receptor (24). GSK-3␤ regulates the progesterone response in Xenopus oocyte meiotic entry, and treating with GSK-3␤ inhibitor enhances the progesterone sensitivity of Xenopus oocytes (16).…”

“…On the other hand, many GSK-3␤ substrates such as Axin and Tau (15), steroid receptors (21,22,24), do not need priming phosphorylation. It was noted that phosphorylation of glucocorticoid receptor serine 404 by GSK-3␤ is also essential for modulating its stability (23). Interestingly, the surrounding amino acid sequences of serine 390 of PR-A share high homology with that of the glucocorticoid receptor serine 404, suggesting a potential recognition motif for GSK-3␤ for this class of proteins.…”