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Decreased protein and mRNA expression of ER stress proteins GRP78 and GRP94 in HepG2 cells over-expressing CYP2E1.
Arch Biochem Biophys. 2006 Mar 15; 447(2):155-66.AB

Abstract

CYP2E1 causes oxidative stress mediated cell death; the latter is one mechanism for endoplasmic reticulum (ER) stress in the cell. Unfolded proteins accumulate during ER stress and ER resident proteins GRP78 and GRP94 protect cells against ER dysfunction. We examined the possible role of GRP78 and GRP94 as protective factors against CYP2E1-mediated toxicity in HepG2 cells expressing CYP2E1 (E47 cells). E47 cells expressed high levels of CYP2E1 protein and catalytic activity which is associated with increased ROS generation, lipid peroxidation and the elevated presence of ubiquinated and aggregated proteins as compared to control HepG2 C34 cells which do not express CYP2E1. The mRNA and protein expression of GRP78 and GRP94 were decreased in E47 cells compared to the C34 cells, which may explain the accumulation of ubiquinated and aggregated proteins. Expression of these GRP proteins was induced with the ER stress agent thapsigargin in E47 cells, and E47 cells were more resistant to the toxicity caused by thapsigargin and calcimycin, possibly due to this upregulation and also because of the high expression of GSH and antioxidant enzymes in E47 cells. Antioxidants such as trolox and N-acetylcysteine increased GRP78 and GRP94 levels in the E47 cells, suggesting that CYP2E1- derived oxidant stress was responsible for down regulation of these GRPs in the E47 cells. Thapsigargin mediated toxicity was decreased in cells treated with the antioxidant trolox indicating a role for oxidative stress in this toxicity. These results suggest that CYP2E1 mediated oxidative stress downregulates the expression of GRP proteins in HepG2 cells and oxidative stress is an important mechanism in causing ER dysfunction in these cells.

Authors+Show Affiliations

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16497268

Citation

Dey, Aparajita, et al. "Decreased Protein and mRNA Expression of ER Stress Proteins GRP78 and GRP94 in HepG2 Cells Over-expressing CYP2E1." Archives of Biochemistry and Biophysics, vol. 447, no. 2, 2006, pp. 155-66.
Dey A, Kessova IG, Cederbaum AI. Decreased protein and mRNA expression of ER stress proteins GRP78 and GRP94 in HepG2 cells over-expressing CYP2E1. Arch Biochem Biophys. 2006;447(2):155-66.
Dey, A., Kessova, I. G., & Cederbaum, A. I. (2006). Decreased protein and mRNA expression of ER stress proteins GRP78 and GRP94 in HepG2 cells over-expressing CYP2E1. Archives of Biochemistry and Biophysics, 447(2), 155-66.
Dey A, Kessova IG, Cederbaum AI. Decreased Protein and mRNA Expression of ER Stress Proteins GRP78 and GRP94 in HepG2 Cells Over-expressing CYP2E1. Arch Biochem Biophys. 2006 Mar 15;447(2):155-66. PubMed PMID: 16497268.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Decreased protein and mRNA expression of ER stress proteins GRP78 and GRP94 in HepG2 cells over-expressing CYP2E1. AU - Dey,Aparajita, AU - Kessova,Irina G, AU - Cederbaum,Arthur I, Y1 - 2006/02/08/ PY - 2005/12/27/received PY - 2006/01/19/revised PY - 2006/01/20/accepted PY - 2006/2/25/pubmed PY - 2006/5/4/medline PY - 2006/2/25/entrez SP - 155 EP - 66 JF - Archives of biochemistry and biophysics JO - Arch Biochem Biophys VL - 447 IS - 2 N2 - CYP2E1 causes oxidative stress mediated cell death; the latter is one mechanism for endoplasmic reticulum (ER) stress in the cell. Unfolded proteins accumulate during ER stress and ER resident proteins GRP78 and GRP94 protect cells against ER dysfunction. We examined the possible role of GRP78 and GRP94 as protective factors against CYP2E1-mediated toxicity in HepG2 cells expressing CYP2E1 (E47 cells). E47 cells expressed high levels of CYP2E1 protein and catalytic activity which is associated with increased ROS generation, lipid peroxidation and the elevated presence of ubiquinated and aggregated proteins as compared to control HepG2 C34 cells which do not express CYP2E1. The mRNA and protein expression of GRP78 and GRP94 were decreased in E47 cells compared to the C34 cells, which may explain the accumulation of ubiquinated and aggregated proteins. Expression of these GRP proteins was induced with the ER stress agent thapsigargin in E47 cells, and E47 cells were more resistant to the toxicity caused by thapsigargin and calcimycin, possibly due to this upregulation and also because of the high expression of GSH and antioxidant enzymes in E47 cells. Antioxidants such as trolox and N-acetylcysteine increased GRP78 and GRP94 levels in the E47 cells, suggesting that CYP2E1- derived oxidant stress was responsible for down regulation of these GRPs in the E47 cells. Thapsigargin mediated toxicity was decreased in cells treated with the antioxidant trolox indicating a role for oxidative stress in this toxicity. These results suggest that CYP2E1 mediated oxidative stress downregulates the expression of GRP proteins in HepG2 cells and oxidative stress is an important mechanism in causing ER dysfunction in these cells. SN - 0003-9861 UR - https://www.unboundmedicine.com/medline/citation/16497268/Decreased_protein_and_mRNA_expression_of_ER_stress_proteins_GRP78_and_GRP94_in_HepG2_cells_over_expressing_CYP2E1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0003-9861(06)00024-5 DB - PRIME DP - Unbound Medicine ER -