The Glycogen Synthase Kinase Inhibitor 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) Is a Partial Agonist of the Aryl Hydrocarbon Receptor

2009 ◽  
Vol 37 (8) ◽  
pp. 1576-1580 ◽  
Author(s):  
Albert Braeuning ◽  
Albrecht Buchmann
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Partial Agonist ◽  
Glycogen Synthase Kinase ◽  
Aryl Hydrocarbon

scholarly journals Glycogen Synthase Kinase 3 Beta Regulates the Human Aryl Hydrocarbon Receptor Cellular Content and Activity

2021 ◽  
Vol 22 (11) ◽  
pp. 6097
Author(s):  
Yujie Yang ◽  
William K. Chan
Keyword(s):  
Protein Degradation ◽  
Aryl Hydrocarbon Receptor ◽  
Gene Transcription ◽  
Target Gene ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Lysosomal Degradation ◽  
Aryl Hydrocarbon ◽  
Cellular Content

The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which is involved in diverse cellular events in humans. The most well-characterized function of AHR is its ability to upregulate gene transcription after exposure to its ligands, such as environmental toxicants, dietary antioxidants, drugs, and endogenous ligands. The cellular content of AHR is partly controlled by its degradation via the ubiquitin–proteasome system and the lysosome-dependent autophagy. We used human cervical cancer (HeLa) cells to investigate how AHR undergoes protein degradation and how its activity is modulated. Since the glycogen synthase kinase 3 beta (GSK3β)-mediated phosphorylation can trigger protein degradation and substrates of GSK3β contain stretches of serine/threonine residues which can be found in AHR, we examined whether degradation and activity of AHR can be controlled by GSK3β. We observed that AHR undergoes the GSK3β-dependent, LC3-mediated lysosomal degradation without ligand treatment. The AHR can be phosphorylated in a GSK3β-dependent manner at three putative sites (S436/S440/S444, S689/S693/T697, and S723/S727/T731), which leads to lysosomal degradation of the AHR protein. Inhibition of the GSK3β activity suppresses the ligand-activated transcription of an AHR target gene in HeLa, human liver cancer (Hep3B), and human breast cancer (MCF-7) cells. Collectively, our findings support that phosphorylation of AHR by GSK3β is essential for the optimal activation of its target gene transcription and this phosphorylation may partake as an “off” switch by subjecting the receptor to lysosomal degradation.

scholarly journals Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

2020 ◽  
Vol 22 (1) ◽  
pp. 141
Author(s):  
George Anderson
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Glycogen Synthase ◽  
Tumour Progression ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Future Research ◽  
Acetyl Coa ◽  
Dynamic Interactions ◽  
Aryl Hydrocarbon ◽  
Metabolic Interactions

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven ‘backward’ conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.

scholarly journals Activation of the aryl hydrocarbon receptor by the widely used Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2)

2014 ◽  
Vol 89 (8) ◽  
pp. 1329-1336 ◽  
Author(s):  
Katrin Frauenstein ◽  
Julia Tigges ◽  
Anatoly A. Soshilov ◽  
Sarah Kado ◽  
Nadeshda Raab ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Kinase Inhibitor ◽  
Src Family Kinase ◽  
Aryl Hydrocarbon

JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes

2008 ◽  
Vol 75 (2) ◽  
pp. 580-588 ◽  
Author(s):  
Zdenek Dvorak ◽  
Radim Vrzal ◽  
Pavla Henklova ◽  
Petra Jancova ◽  
Eva Anzenbacherova ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Partial Agonist ◽  
Human Hepatocytes ◽  
Primary Human Hepatocytes ◽  
Aryl Hydrocarbon

THE JUN N-TERMINAL KINASE INHIBITOR SP600125 IS A LIGAND AND ANTAGONIST OF THE ARYL HYDROCARBON RECEPTOR

2003 ◽  
Vol 31 (11) ◽  
pp. 1279-1282 ◽  
Author(s):  
Aby Joiakim ◽  
Patricia A. Mathieu ◽  
Christine Palermo ◽  
Thomas A. Gasiewicz ◽  
John J. Reiners
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Kinase Inhibitor ◽  
Aryl Hydrocarbon
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