scholarly journals GSK-3: A Bifunctional Role in Cell Death Pathways

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Keith M. Jacobs ◽  
Sandeep R. Bhave ◽  
Daniel J. Ferraro ◽  
Jerry J. Jaboin ◽  
Dennis E. Hallahan ◽  
...  
Keyword(s):  
Cell Death ◽  
Glycogen Synthase ◽  
Molecular Target ◽  
Glycogen Synthase Kinase 3 ◽  
Cellular Functions ◽  
Cell Death Pathways ◽  
Wide Range ◽  
Growth Metabolism ◽  
Significant Attention

Although glycogen synthase kinase-3 beta (GSK-3β) was originally named for its ability to phosphorylate glycogen synthase and regulate glucose metabolism, this multifunctional kinase is presently known to be a key regulator of a wide range of cellular functions. GSK-3βis involved in modulating a variety of functions including cell signaling, growth metabolism, and various transcription factors that determine the survival or death of the organism. Secondary to the role of GSK-3βin various diseases including Alzheimer’s disease, inflammation, diabetes, and cancer, small molecule inhibitors of GSK-3βare gaining significant attention. This paper is primarily focused on addressing the bifunctional or conflicting roles of GSK-3βin both the promotion of cell survival and of apoptosis. GSK-3βhas emerged as an important molecular target for drug development.

scholarly journals Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3

2019 ◽  
Vol 317 (6) ◽  
pp. C1289-C1303 ◽  
Author(s):  
Mahboubeh S. Noori ◽  
Pooja M. Bhatt ◽  
Maria C. Courreges ◽  
Davoud Ghazanfari ◽  
Chaz Cuckler ◽  
...  
Keyword(s):  
Design Space ◽  
Potent Inhibitor ◽  
Glycogen Synthase ◽  
Selective Inhibition ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Cellular Functions ◽  
Starting Point ◽  
Potential Therapeutics

Glycogen synthase kinase-3 (GSK-3) is a multitasking protein kinase that regulates numerous critical cellular functions. Not surprisingly, elevated GSK-3 activity has been implicated in a host of diseases including pathological inflammation, diabetes, cancer, arthritis, asthma, bipolar disorder, and Alzheimer’s. Therefore, reagents that inhibit GSK-3 activity provide a means to investigate the role of GSK-3 in cellular physiology and pathophysiology and could become valuable therapeutics. Finding a potent inhibitor of GSK-3 that can selectively target this kinase, among over 500 protein kinases in the human genome, is a significant challenge. Thus there remains a critical need for the identification of selective inhibitors of GSK-3. In this work, we introduce a novel small organic compound, namely COB-187, which exhibits potent and highly selective inhibition of GSK-3. Specifically, this study 1) utilized a molecular screen of 414 kinase assays, representing 404 unique kinases, to reveal that COB-187 is a highly potent and selective inhibitor of GSK-3; 2) utilized a cellular assay to reveal that COB-187 decreases the phosphorylation of canonical GSK-3 substrates indicating that COB-187 inhibits cellular GSK-3 activity; and 3) reveals that a close isomer of COB-187 is also a selective and potent inhibitor of GSK-3. Taken together, these results demonstrate that we have discovered a region of chemical design space that contains novel GSK-3 inhibitors. These inhibitors will help to elucidate the intricate function of GSK-3 and can serve as a starting point for the development of potential therapeutics for diseases that involve aberrant GSK-3 activity.

scholarly journals The Role of Mitophagy in Regulating Cell Death

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Sunao Li ◽  
Jiaxin Zhang ◽  
Chao Liu ◽  
Qianliang Wang ◽  
Jun Yan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytosolic Calcium ◽  
Cellular Functions ◽  
Power Generators ◽  
Unfolded Protein ◽  
Mitochondrial Homeostasis ◽  
Cell Death Pathways ◽  
Health And Disease ◽  
Protein Response

Mitochondria are multifaceted organelles that serve to power critical cellular functions, including act as power generators of the cell, buffer cytosolic calcium overload, production of reactive oxygen species, and modulating cell survival. The structure and the cellular location of mitochondria are critical for their function and depend on highly regulated activities such as mitochondrial quality control (MQC) mechanisms. The MQC is regulated by several sets of processes: mitochondrial biogenesis, mitochondrial fusion and fission, mitophagy, and other mitochondrial proteostasis mechanisms such as mitochondrial unfolded protein response (mtUPR) or mitochondrial-derived vesicles (MDVs). These processes are important for the maintenance of mitochondrial homeostasis, and alterations in the mitochondrial function and signaling are known to contribute to the dysregulation of cell death pathways. Recent studies have uncovered regulatory mechanisms that control the activity of the key components for mitophagy. In this review, we discuss how mitophagy is controlled and how mitophagy impinges on health and disease through regulating cell death.

scholarly journals Underlying mechanisms of glucocorticoid-induced β-cell death and dysfunction: a new role for glycogen synthase kinase 3

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Etienne Delangre ◽  
Junjun Liu ◽  
Stefania Tolu ◽  
Kamel Maouche ◽  
Mathieu Armanet ◽  
...  
Keyword(s):  
Cell Death ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Β Cells ◽  
Β Cell ◽  
Protein Levels ◽  
Underlying Mechanisms ◽  
Apoptotic Effects

AbstractGlucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in β-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of β-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced β-cell death and impaired insulin secretion. Further, we unraveled the underlying mechanisms of GC-GSK3 crosstalk. We showed that GSK3 is marginally implicated in the nuclear localization of GC receptor (GR) upon ligand binding. Furthermore, we showed that GSK3 regulates the expression of GR at mRNA and protein levels. Finally, we dissected the proper contribution of each GSK3 isoform and showed that GSK3β isoform is sufficient to mediate the pro-apoptotic effects of GCs in β-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic β-cells.

scholarly journals Investigating and re-evaluating the role of glycogen synthase kinase 3 beta kinase as a molecular target for cardioprotection by using novel pharmacological inhibitors

2019 ◽  
Vol 115 (7) ◽  
pp. 1228-1243 ◽  
Author(s):  
Panagiota-Efstathia Nikolaou ◽  
Kerstin Boengler ◽  
Panagiotis Efentakis ◽  
Konstantina Vouvogiannopoulou ◽  
Anastasia Zoga ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Molecular Target ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

2021 ◽  
Vol 22 (5) ◽  
pp. 2754
Author(s):  
Naila Qayyum ◽  
Muhammad Haseeb ◽  
Moon Suk Kim ◽  
Sangdun Choi
Keyword(s):  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Signaling Complex ◽  
Current Review ◽  
Wide Range ◽  
Range Of Functions ◽  
Species Production ◽  
And Oxidative Stress ◽  
Significant Attention

Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.

scholarly journals Cell Death Pathways and Viruses: Role of microRNAs

2021 ◽  
Author(s):  
Javid Sadri Nahand ◽  
Layla Shojaie ◽  
Seyed Amirreza Akhlagh ◽  
Mohammad Saeid Ebrahimi ◽  
Hamid Reza Mirzaei ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Death Pathways

scholarly journals Cell Death and Survival Pathways Involving ATM Protein Kinase

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1581
Author(s):  
Toshihiko Aki ◽  
Koichi Uemura
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Genotoxic Stress ◽  
Short Review ◽  
Research Progress ◽  
Cellular Protection ◽  
Cellular Survival ◽  
Cell Death Pathways ◽  
Wide Range ◽  
Atm Protein

Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell death, can occur in both separate and simultaneous manners. ATM (ataxia telangiectasia mutated) kinase (hereafter referred to as ATM) is a protein kinase that plays central roles in the induction of cell death during genotoxic stresses. It has long been considered that ATM mediates DNA damage-induced cell death through inducing apoptosis. However, recent research progress in cell death modality is now revealing ATM-dependent cell death pathways that consist of not only apoptosis but also necroptosis, ferroptosis, and dysfunction of autophagy, a cellular survival mechanism. In this short review, we intend to provide a brief outline of cell death mechanisms in which ATM is involved, with emphasis on pathways other than apoptosis.

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