scholarly journals Glycogen Synthase Kinase‐3β Modulation of Basal Aryl Hydrocarbon Receptor Protein Levels in HeLa Cells

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Yujie Yang ◽  
William K. Chan
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Hela Cells ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Receptor Protein ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Levels ◽  
Aryl Hydrocarbon

scholarly journals Glycogen synthase kinase 3β mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1

2010 ◽  
Vol 206 (2) ◽  
pp. 171-181 ◽  
Author(s):  
Sanhua Leng ◽  
Wenshuo Zhang ◽  
Yanbin Zheng ◽  
Ziva Liberman ◽  
Christopher J Rhodes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Molecular Mechanism ◽  
High Glucose ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Insulin Receptor Substrate ◽  
Glycogen Synthase Kinase 3Β ◽  
Proteasome Degradation ◽  
Protein Levels

High glucose (HG) has been shown to induce insulin resistance in both type 1 and type 2 diabetes. However, the molecular mechanism behind this phenomenon is unknown. Insulin receptor substrate (IRS) proteins are the key signaling molecules that mediate insulin's intracellular actions. Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. We have identified glycogen synthase kinase 3β (GSK3β or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine332 phosphorylation, ubiquitination, and degradation of IRS1. Overexpression of IRS1 with mutation of serine332 to alanine partially prevents HG-induced IRS1 degradation. Furthermore, overexpression of constitutively active GSK3β was sufficient to induce IRS1 degradation. Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3β contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1.

scholarly journals Selective Autophagy Maintains the Aryl Hydrocarbon Receptor Levels in HeLa Cells: A Mechanism That Is Dependent on the p23 Co-Chaperone

2020 ◽  
Vol 21 (10) ◽  
pp. 3449
Author(s):  
Yujie Yang ◽  
William K. Chan
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Hela Cells ◽  
Stem Cell Differentiation ◽  
26S Proteasome ◽  
Chemical Agent ◽  
Physical Interaction ◽  
Hematopoietic Stem ◽  
Selective Autophagy ◽  
Protein Levels ◽  
Aryl Hydrocarbon

The aryl hydrocarbon receptor (AHR) is an environmental sensing molecule which impacts diverse cellular functions such as immune responses, cell growth, respiratory function, and hematopoietic stem cell differentiation. It is widely accepted that the degradation of AHR by 26S proteasome occurs after ligand activation. Recently, we discovered that HeLa cells can modulate the AHR levels via protein degradation without exogenous treatment of a ligand, and this degradation is particularly apparent when the p23 content is down-regulated. Inhibition of autophagy by a chemical agent (such as chloroquine, bafilomycin A1, or 3-methyladenine) increases the AHR protein levels in HeLa cells whereas activation of autophagy by short-term nutrition deprivation reduces its levels. Treatment of chloroquine retards the degradation of AHR and triggers physical interaction between AHR and LC3B. Knockdown of LC3B suppresses the chloroquine-mediated increase of AHR. Down-regulation of p23 promotes AHR degradation via autophagy with no change of the autophagy-related gene expression. Although most data in this study were derived from HeLa cells, human lung (A549), liver (Hep3B), and breast (T-47D and MDA-MB-468) cells also exhibit AHR levels sensitive to chloroquine treatment and AHR–p62/LC3 interactions. Here we provide evidence supporting that AHR undergoes the p62/LC3-mediated selective autophagy in HeLa cells.

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 SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia

2017 ◽  
Vol 292 (18) ◽  
pp. 7452-7461 ◽  
Author(s):  
Tomeka Suber ◽  
Jianxin Wei ◽  
Anastasia M. Jacko ◽  
Ina Nikolli ◽  
Yutong Zhao ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Proteasomal Degradation ◽  
Lung Epithelial Cells ◽  
Glycogen Synthase Kinase ◽  
Acceptor Site ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Subunit ◽  
Protein Levels ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein

Glycogen synthase kinase-3β (GSK3β) has diverse biological roles including effects on cellular differentiation, migration, and inflammation. GSK3β phosphorylates proteins to generate phosphodegrons necessary for recognition by Skp1/Cullin-1/F-box (SCF) E3 ubiquitin ligases leading to subsequent proteasomal degradation of these substrates. However, little is known regarding how GSK3β protein stability itself is regulated and how its stability may influence inflammation. Here we show that GSK3β is degraded by the ubiquitin-proteasome pathway in murine lung epithelial cells through lysine 183 as an acceptor site for K48 polyubiquitination. We have identified FBXO17 as an F-box protein subunit that recognizes and mediates GSK3β polyubiquitination. Both endogenous and ectopically expressed FBXO17 associate with GSK3β, and its overexpression leads to decreased protein levels of GSK3β. Silencing FBXO17 gene expression increased the half-life of GSK3β in cells. Furthermore, overexpression of FBXO17 inhibits agonist-induced release of keratinocyte-derived cytokine (KC) and interleukin-6 (IL-6) production by cells. Thus, the SCFFBXO17 E3 ubiquitin ligase complex negatively regulates inflammation by targeting GSK3β in lung epithelia.

Protein levels of β-catenin and activation state of glycogen synthase kinase-3β in major depression. A study with postmortem prefrontal cortex

2012 ◽  
Vol 136 (1-2) ◽  
pp. 185-188 ◽  
Author(s):  
Félicien Karege ◽  
Nader Perroud ◽  
Sandra Burkhardt ◽  
Rafael Fernandez ◽  
Eladia Ballmann ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Major Depression ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Levels
Sign in / Sign up

Export Citation Format

Share Document