The GSK3-NRF2 Axis in Suicide

Mutations in the genes coding for tryptophan-hydrolase-2 and the scaffold protein FKBP5 are associated with an increased risk of suicide. The mutation in both cases enhances the enzymatic activity of glycogen synthase kinase-3 (GSK3). Conversely, anti-suicidal medications, such as lithium, clozapine, and ketamine, indirectly inhibit the activity of GSK3. When GSK3 is active, it promotes the metabolic removal of the transcription factor NRF2 (nuclear factor erythroid 2-related factor-2), which suppresses the transcription of multiple genes that encode anti-oxidative and anti-inflammatory proteins. Notably, several suicide-biomarkers bear witness to an ongoing inflammatory process. Moreover, alterations in serum lipid levels measured in suicidal individuals are mirrored by data obtained in mice with genetic deletion of the NRF2 gene. Inflammation is presumably causally related to both dysphoria and anger, two factors relevant for suicide ideation and attempt. Preventing the catabolism of NRF2 could be a strategy to obtain novel suicide-prophylactic medications. Possible candidates are minocycline and nicotinic-α7 agonists. The antibiotic minocycline indirectly activates NRF2-transcriptional activity, whereas the activation of nicotinic-α7 receptors indirectly inhibits GSK3.

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The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

Biochemical Society Transactions ◽

10.1042/bst20150069 ◽

2015 ◽

Vol 43 (4) ◽

pp. 687-689 ◽

Cited By ~ 93

Author(s):

Maria A. O’Connell ◽

John D. Hayes

Keyword(s):

Small Molecules ◽

Glycogen Synthase ◽

Antioxidant Response ◽

Research Area ◽

Glycogen Synthase Kinase 3 ◽

Related Factor ◽

Nuclear Factor ◽

Ubiquitin Protein Ligase ◽

Health And Disease ◽

Transcription Factor Nuclear Factor

The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, with gene called NFE2L2) is a master regulator of the antioxidant response. In the last decade, interest has intensified in this research area as its importance in several physiological and pathological processes has become widely recognized; these include redox signalling and redox homoeostasis, drug metabolism and disposition, intermediary metabolism, cellular adaptation to stress, chemoprevention and chemoresistance, toxicity, inflammation, neurodegeneration, lipogenesis and aging. Regulation of Nrf2 is complex and although much attention has focussed on its repression by Kelch-like ECH-associated protein-1 (Keap1), recently it has become increasingly apparent that it is also controlled by cross-talk with other signalling pathways including the glycogen synthase kinase-3 (GSK-3)−β-transducin repeat-containing protein (β-TrCP) axis, ERAD (endoplasmic reticulum-associated degradation)-associated E3 ubiquitin-protein ligase (Hrd1, also called synoviolin), nuclear factor-kappa B (NF-κB), Notch and AMP kinase. Due to its beneficial role in several diseases, Nrf2 has become a major therapeutic target, with novel natural, synthetic and targeted small molecules currently under investigation to modulate the pathway and in clinical trials.

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Oxidative stress-induced downregulation of glycogen synthase kinase 3 beta in fetal membranes promotes cellular senescence†

Biology of Reproduction ◽

10.1093/biolre/ioz119 ◽

2019 ◽

Vol 101 (5) ◽

pp. 1018-1030 ◽

Cited By ~ 7

Author(s):

Narmada Lavu ◽

Lauren Richardson ◽

Enkhtuya Radnaa ◽

Talar Kechichian ◽

Rheanna Urrabaz-Garza ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Cycle ◽

Western Blot ◽

Nuclear Translocation ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Fetal Membrane ◽

Related Factor ◽

Beta Catenin

Abstract Objective Oxidative stress (OS)-induced stress signaler p38 mitogen-activated protein kinase (p38MAPK) activation and fetal membrane senescence are associated with parturition. This study determined changes in glycogen synthase kinase 3 beta (GSK3β) and its regulation by p38MAPK in effecting senescence to further delineate the molecular mechanism involved in senescence. Methods Primary human amnion epithelial cells and amnion mesenchymal cells were treated with cigarette smoke extract (CSE, OS inducer). Expression of total and phosphorylated GSK3β and p38MAPK, and that of GSK3β’s downstream targets: beta-catenin (β-Cat) and nuclear factor erythroid 2-related factor 2 (Nrf2) (western blot analysis), cell cycle regulation and senescence (flow cytometry) were determined. The specificity of GSK3β and p38MAPK’s mechanistic role was tested by co-treating cells with their respective inhibitors, CHIR99021 and SB203580. Exosomal secretion of β-Cat from OS-induced cells was confirmed by immunofluorescence confocal microscopy and western blot. Results OS induced by CSE resulted in phosphorylation of GSK3β (inactivation) and p38MAPK (activation) that was associated with cell cycle arrest and senescence. Inhibitors to GSK3β and p38MAPK verified their roles. Glycogen synthase kinase 3 beta inactivation was associated with nuclear translocation of antioxidant Nrf2 and exosomal secretion of β-Cat. Conclusions OS-induced P-p38MAPK activation is associated with functional downregulation of GSK3β and arrest of cell cycle progression and senescence of amnion cells. Lack of nuclear translocation of β-Cat and its excretion via exosomes further supports the postulation that GSK3β down-regulation by p38MAPK may stop cell proliferation preceding cell senescence. A better understanding of molecular mechanisms of senescence will help develop therapeutic strategies to prevent preterm birth.

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Pro-inflammatory mediator leukotriene D4 induces transcriptional activity of potentially oncogenic genes

Biochemical Society Transactions ◽

10.1042/bst0330698 ◽

2005 ◽

Vol 33 (4) ◽

pp. 698-700 ◽

Cited By ~ 12

Author(s):

M. Mezhybovska ◽

K. Wikström ◽

J.F. Öhd ◽

A. Sjölander

Keyword(s):

Transcriptional Activity ◽

Inflammatory Mediator ◽

Glycogen Synthase ◽

Leukotriene D4 ◽

Kinase Activation ◽

T Cell Factor ◽

Inflammatory Conditions ◽

Increased Risk ◽

Phosphoinositide 3 Kinase ◽

Enhancer Factor

The inflammatory mediator LTD4 (leukotriene D4) is present at high levels in many inflammatory conditions, and areas of chronic inflammation have an increased risk for subsequent cancer development. We demonstrate here that following LTD4 stimulation, β-catenin is translocated to the nucleus, triggering the transcriptional activity of the TCF (T-cell factor)/LEF (lymphoid enhancer factor) family of transcription factors. These events are dependent on phosphoinositide-3 kinase activation and glycogen synthase kinase inhibition. Our data suggest that, similar to Wnt signalling, LTD4 increases free β-catenin and targets it to the nucleus.

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