scholarly journals Regulation of thymocyte β-selection, development and positive selection by glycogen synthase kinase-3

2019 ◽  
Author(s):  
Michael J. Parsons ◽  
Satish Patel ◽  
Bradley W. Doble ◽  
Pamela S. Ohashi ◽  
James R. Woodgett
Keyword(s):  
Positive Selection ◽  
Glycogen Synthase ◽  
Functional Expression ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphatidylinositol 3 Kinase ◽  
Double Positive ◽  
Serine Threonine Kinase ◽  
Gsk 3Β ◽  
Knockout Animals

AbstractGlycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase, that exists as two isoforms in mammals, GSK-3α and GSK-3β, that are key downstream mediators of the phosphatidylinositol 3’ kinase, Wnt, Notch and other pathways. Here, we report that simultaneous inactivation of both GSK-3α and GSK-3β during early thymocyte ontogeny has profound effects on both β-selection and positive selection, key checkpoints essential to producing functionally mature αβ T cells. Conditional GSK-3α/β knockout animals (LckCre+ GSK-3αβfl/fl) possessed pre-double positive (pre-DP) thymocytes (CD4−CD8−CD117−CD25−) with compromised TCRβ chain expression along with elevated levels of β-catenin and reduced Notch activity. β-selection was impaired allowing pre-DP thymocytes to differentiate to DP thymocytes (CD4+CD8+) while bypassing strict requirements for productive TCRβ chain rearrangements and functional expression. Also impaired was the requisite pre-TCR and Notch-mediated expansion that normally precedes differentiation to the DP stage. Consequently, LckCre+ GSK-3αβfl/fl mice initially generated fewer DP thymocytes that expressed significantly reduced levels of mature TCR. The aberrant DP thymocytes expressed high levels of the pro-survival Bcl-2 family member Mcl-1, failed positive selection and accumulated as CD4hiCD8lo positive selection intermediates resulting in loss of both mature CD4 and CD8 lineages. LckCre+ GSK-3αβfl/fl mice succumbed to oligoclonal peripheral lymphomas with high penetrance. These data reveal essential roles for GSK-3 in several checkpoints of early T cell development.

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.

scholarly journals Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1120 ◽  
Author(s):  
Manisha Gupte ◽  
Prachi Umbarkar ◽  
Anand Prakash Singh ◽  
Qinkun Zhang ◽  
Sultan Tousif ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Total Period ◽  
Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

scholarly journals Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1α and Mediates Its Destabilization in a VHL-Independent Manner

2007 ◽  
Vol 27 (9) ◽  
pp. 3253-3265 ◽  
Author(s):  
Daniela Flügel ◽  
Agnes Görlach ◽  
Carine Michiels ◽  
Thomas Kietzmann
Keyword(s):  
Protein Kinase ◽  
Metabolic Diseases ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Hypoxia Inducible Factor ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Independent Manner ◽  
Von Hippel Lindau ◽  
Gsk 3Β

ABSTRACT Hypoxia-inducible transcription factor 1α (HIF-1α) is a key player in the response to hypoxia. Additionally, HIF-1α responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1α is not a direct substrate for this kinase. Therefore, we investigated whether the protein kinase B target glycogen synthase kinase 3 (GSK-3) may have an impact on HIF-1α. We found that the inhibition or depletion of GSK-3 induced HIF-1α whereas the overexpression of GSK-3β reduced HIF-1α. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1α. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1α degradation in a VHL-independent manner. In line with these observations, the inhibition of the proteasome reversed the GSK-3 effects, indicating that GSK-3 may target HIF-1α to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1α stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.

Glycogen Synthase Kinase 3 Beta (GSK-3β) as a Therapeutic Target in NeuroAIDS

2006 ◽  
Vol 2 (1) ◽  
pp. 93-96 ◽  
Author(s):  
Stephen Dewhurst ◽  
Sanjay B. Maggirwar ◽  
Giovanni Schifitto ◽  
Howard E. Gendelman ◽  
Harris A. Gelbard
Keyword(s):  
Therapeutic Target ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Gsk 3Β

scholarly journals Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci

2010 ◽  
Vol 285 (53) ◽  
pp. 41337-41347 ◽  
Author(s):  
Anthony P. Popkie ◽  
Leigh C. Zeidner ◽  
Ashley M. Albrecht ◽  
Anthony D'Ippolito ◽  
Sigrid Eckardt ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Pi3k Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3
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