scholarly journals Identification of Domains Responsible for Ubiquitin-Dependent Degradation of dMyc by Glycogen Synthase Kinase 3β and Casein Kinase 1 Kinases

2009 ◽  
Vol 29 (12) ◽  
pp. 3424-3434 ◽  
Author(s):  
Margherita Galletti ◽  
Sara Riccardo ◽  
Federica Parisi ◽  
Carlina Lora ◽  
Mahesh Kumar Saqcena ◽  
...  
Keyword(s):  
Compound Eye ◽  
Glycogen Synthase ◽  
Physiological Role ◽  
Casein Kinase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Casein Kinase 1 ◽  
The One

ABSTRACT In the present study, we report that ubiquitin-mediated degradation of dMyc, the Drosophila homologue of the human c-myc proto-oncogene, is regulated in vitro and in vivo by members of the casein kinase 1 (CK1) family and by glycogen synthase kinase 3β (GSK3β). Using Drosophila S2 cells, we demonstrate that CK1α promotes dMyc ubiquitination and degradation with a mechanism similar to the one mediated by GSK3β in vertebrates. Mutation of ck1α or -ε or sgg/gsk3β in Drosophila wing imaginal discs results in the accumulation of dMyc protein, suggesting a physiological role for these kinases in vivo. Analysis of the dMyc amino acid sequence reveals the presence of conserved domains containing potential phosphorylation sites for mitogen kinases, GSK3β, and members of the CK1 family. We demonstrate that mutations of specific residues within these phosphorylation domains regulate dMyc protein stability and confer resistance to degradation by CK1α and GSK3β kinases. Expression of the dMyc mutants in the compound eye of the adult fly results in a visible defect that is attributed to the effect of dMyc on growth, cell death, and inhibition of ommatidial differentiation.

Synthesis of benzimidazole-based 1,3,4-oxadiazole-1,2,3-triazole conjugates as glycogen synthase kinase-3β inhibitors with antidepressant activity in in vivo models

RSC Advances ◽  
2016 ◽  
Vol 6 (49) ◽  
pp. 43345-43355 ◽  
Author(s):  
Mushtaq A. Tantray ◽  
Imran Khan ◽  
Hinna Hamid ◽  
Mohammad Sarwar Alam ◽  
Abhijeet Dhulap ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Antidepressant Activity ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
In Vivo Models ◽  
Gsk 3Β

Synthesized benzimidazole based 1,3,4-oxadiazole-1,2,3-triazole conjugates were found to inhibit GSK-3β activityin vitroand exhibit antidepressant-like activity inin vivostudies.

Antibodies against β-amyloid reduce aβ oligomers, glycogen synthase kinase-3β activation and τ phosphorylation in vivo and in vitro

2006 ◽  
Vol 83 (3) ◽  
pp. 374-384 ◽  
Author(s):  
Qiu-Lan Ma ◽  
Giselle P. Lim ◽  
Marni E. Harris-White ◽  
Fusheng Yang ◽  
Surendra S. Ambegaokar ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Aβ Oligomers ◽  
Β Amyloid

scholarly journals Interaction of Glycogen Synthase Kinase 3β with the DF3/MUC1 Carcinoma-Associated Antigen and β-Catenin

1998 ◽  
Vol 18 (12) ◽  
pp. 7216-7224 ◽  
Author(s):  
Yongqing Li ◽  
Ajit Bharti ◽  
Dongshu Chen ◽  
Jianlin Gong ◽  
Donald Kufe
Keyword(s):  
Cell Adhesion Molecule ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Muc1 Expression ◽  
Glycogen Synthase Kinase 3Β ◽  
Apparent Effect ◽  
Human Carcinomas ◽  
E Cadherin

ABSTRACT The DF3/MUC1 mucin-like glycoprotein is highly overexpressed in human carcinomas. Recent studies have demonstrated that the cytoplasmic domain of MUC1 interacts with β-catenin. Here we show that MUC1 associates with glycogen synthase kinase 3β (GSK3β). GSK3β binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3β decreases binding of MUC1 to β-catenin in vitro and in vivo. GSK3β-mediated phosphorylation of MUC1 had no apparent effect on β-catenin levels or the transcriptional coactivation function of β-catenin. The results, however, demonstrate that MUC1 expression decreases binding of β-catenin to the E-cadherin cell adhesion molecule. Negative regulation of the β-catenin–MUC1 interaction by GSK3β is associated with restoration of the complex between β-catenin and E-cadherin. These findings indicate that GSK3β decreases the interaction of MUC1 with β-catenin and that overexpression of MUC1 in the absence of GSK3β activity inhibits formation of the E-cadherin–β-catenin complex.

scholarly journals GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 610
Author(s):  
Robin Park ◽  
Andrew L. Coveler ◽  
Ludimila Cavalcante ◽  
Anwaar Saeed
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
In Vivo Models ◽  
Gsk 3Β ◽  
Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

Microtubule-associated protein 1B phosphorylation by glycogen synthase kinase 3β is induced during PC12 cell differentiation

2001 ◽  
Vol 114 (23) ◽  
pp. 4273-4284 ◽  
Author(s):  
Robert G. Goold ◽  
Phillip R. Gordon-Weeks
Keyword(s):  
Cell Differentiation ◽  
Pc12 Cell ◽  
Glycogen Synthase ◽  
Axon Outgrowth ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Cell Extracts ◽  
Neurite Formation ◽  
Reduced Mobility

In recent studies we have demonstrated that glycogen synthase kinase 3β (GSK3β) and its substrate microtubule-associated protein 1B (MAP1B) regulate the microtubule cytoskeleton during axon outgrowth. To further examine the role GSK3β plays in axon outgrowth we investigated the expression of GSK3β and its activity towards MAP1B during nerve growth factor (NGF)-stimulated PC12 cell differentiation. Levels of GSK3β expression increase relatively little during the course of differentiation. However, the expression of a novel GSK3β isoform characterised by a reduced mobility on SDS gels is induced by NGF. Expression of this isoform and the GSK3β-phosphorylated isoform of MAP1B (MAP1B-P) are induced in parallel in response to NGF. This increase lags behind initial neurite formation and the expression of MAP1B in these cells by about two days and coincides with a period when the majority of cells are extending existing neurites. MAP1B and GSK3β are expressed throughout the PC12 cell but MAP1B-P expression is restricted to the growth cones and neurites. Consistent with these observations, we find that neurite extension is more sensitive to the GSK3 inhibitor Li+ than neurite formation and that this correlates with an inhibition of MAP1B phosphorylation. Additionally, GSK3β from PC12 cells not exposed to NGF can not phosphorylate MAP1B in vitro. However, a soluble factor in differentiated PC12 cell extracts depleted of GSK3β can activate MAP1B phosphorylation from undifferentiated cell extracts otherwise devoid of kinase activity. These experiments provide evidence for an NGF-mediated regulation of MAP1B phosphorylation in growing neurites by the induction of a novel isoform of GSK3β.

scholarly journals Genetic or pharmacological superoxide-hydrogen peroxide imbalances modulate the in vitro effects of lithium on glycogen synthase kinase-3β

Gene ◽  
2018 ◽  
Vol 655 ◽  
pp. 48-55 ◽  
Author(s):  
Fernanda Barbisan ◽  
Verônica Farina Azzolin ◽  
Gustavo Cardenas Monteiro ◽  
Cibele F. Teixeira ◽  
Moisés Henrique Mastella ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
In Vitro Effects
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