| Glycogen synthase kinase-3 plays a central role in mediating glucocorticoid-induced apoptosis. | |
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MedLine Citation:
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PMID: 20371704 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Rachel Spokoini; Shlomit Kfir-Erenfeld; Eitan Yefenof; Ronit Vogt Sionov |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-04-06 |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 24 ISSN: 1944-9917 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-26 Completed Date: 2010-09-02 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: United States |
Other Details:
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Languages: eng Pagination: 1136-50 Citation Subset: IM |
Affiliation:
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The Lautenberg Center of Immunology, Institute of Medical Research, Faculty of Medicine, Hebrew University, Jerusalem, Israel. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Apoptosis Regulatory Proteins / metabolism Cell Line Dexamethasone / pharmacology Drug Resistance, Neoplasm / drug effects Enzyme Activation / drug effects Glucocorticoids / pharmacology* Glycogen Synthase Kinase 3 / antagonists & inhibitors, metabolism* Humans Ligands Membrane Proteins / metabolism Mice Models, Biological Protein Binding / drug effects Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-akt / metabolism Receptors, Glucocorticoid / metabolism Receptors, Notch / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Apoptosis Regulatory Proteins; 0/Bcl-2-like protein 11; 0/Glucocorticoids; 0/Ligands; 0/Membrane Proteins; 0/Protein Kinase Inhibitors; 0/Proto-Oncogene Proteins; 0/Receptors, Glucocorticoid; 0/Receptors, Notch; 50-02-2/Dexamethasone; EC 2.7.1.37/glycogen synthase kinase 3 alpha; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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