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Title: Activation of ERK1/2 and p38 kinases by polycyclic aromatic hydrocarbons in rat liver epithelial cells is associated with induction of apoptosis

Abstract

Deregulation of various signaling pathways, linked either to induction of cell proliferation or to modulation of cellular differentiation and apoptosis, has been proposed to contribute to carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). In the present study, we investigated effects of the PAHs previously shown to induce cell proliferation and/or apoptosis in contact-inhibited rat liver epithelial WB-F344 cells, with an aim to define the role of mitogen-activated protein kinases in both events. We found that only strong genotoxin dibenzo[a,l]pyrene (DBalP) activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 kinase, but not c-Jun N-terminal kinases (JNKs), at concentrations inducing both apoptosis and phosphorylation of p53 tumor suppressor at serine 15 residue. In contrast, the PAHs stimulating cell proliferation in WB-F344 cell line had no effect on activation of ERK1/2, p38 or JNKs. Synthetic inhibitors of ERK1/2 activation (U0126) or p38 kinase activity (SB203580) prevented both apoptosis and induction of p53 phosphorylation by DBalP. Pifithrin-{alpha}, inhibitor of p53 transcriptional activity, prevented induction of apoptosis and activation of ERK1/2 and p38. Taken together, our data suggest that both ERK1/2 and p38 are activated in response to DBalP and that they might be involved in regulation of cellular response to DNA damage inducedmore » by DBalP, while neither kinase is involved in the release from contact inhibition induced by PAHs.« less

Authors:
 [1];  [2];  [3];  [1];  [1];  [1];  [4]
  1. Laboratory of Cytokinetics, Institute of Biophysics, ASCR, 612 65 Brno (Czech Republic)
  2. (Czech Republic)
  3. Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno (Czech Republic)
  4. Laboratory of Cytokinetics, Institute of Biophysics, ASCR, 612 65 Brno (Czech Republic) and Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno (Czech Republic). E-mail: vondracek@ibp.cz
Publication Date:
OSTI Identifier:
20783443
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 211; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2005.06.007; PII: S0041-008X(05)00371-6; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CELL PROLIFERATION; DNA DAMAGES; INDUCTION; LIVER; NEOPLASMS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; POLYCYCLIC AROMATIC HYDROCARBONS; PYRENE; RATS; SERINE

Citation Formats

Andrysik, Zdenek, Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Machala, Miroslav, Chramostova, Katerina, Hofmanova, Jirina, Kozubik, Alois, and Vondracek, Jan. Activation of ERK1/2 and p38 kinases by polycyclic aromatic hydrocarbons in rat liver epithelial cells is associated with induction of apoptosis. United States: N. p., 2006. Web. doi:10.1016/j.taap.2005.06.007.
Andrysik, Zdenek, Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Machala, Miroslav, Chramostova, Katerina, Hofmanova, Jirina, Kozubik, Alois, & Vondracek, Jan. Activation of ERK1/2 and p38 kinases by polycyclic aromatic hydrocarbons in rat liver epithelial cells is associated with induction of apoptosis. United States. doi:10.1016/j.taap.2005.06.007.
Andrysik, Zdenek, Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Machala, Miroslav, Chramostova, Katerina, Hofmanova, Jirina, Kozubik, Alois, and Vondracek, Jan. Wed . "Activation of ERK1/2 and p38 kinases by polycyclic aromatic hydrocarbons in rat liver epithelial cells is associated with induction of apoptosis". United States. doi:10.1016/j.taap.2005.06.007.
@article{osti_20783443,
title = {Activation of ERK1/2 and p38 kinases by polycyclic aromatic hydrocarbons in rat liver epithelial cells is associated with induction of apoptosis},
author = {Andrysik, Zdenek and Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno and Machala, Miroslav and Chramostova, Katerina and Hofmanova, Jirina and Kozubik, Alois and Vondracek, Jan},
abstractNote = {Deregulation of various signaling pathways, linked either to induction of cell proliferation or to modulation of cellular differentiation and apoptosis, has been proposed to contribute to carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). In the present study, we investigated effects of the PAHs previously shown to induce cell proliferation and/or apoptosis in contact-inhibited rat liver epithelial WB-F344 cells, with an aim to define the role of mitogen-activated protein kinases in both events. We found that only strong genotoxin dibenzo[a,l]pyrene (DBalP) activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 kinase, but not c-Jun N-terminal kinases (JNKs), at concentrations inducing both apoptosis and phosphorylation of p53 tumor suppressor at serine 15 residue. In contrast, the PAHs stimulating cell proliferation in WB-F344 cell line had no effect on activation of ERK1/2, p38 or JNKs. Synthetic inhibitors of ERK1/2 activation (U0126) or p38 kinase activity (SB203580) prevented both apoptosis and induction of p53 phosphorylation by DBalP. Pifithrin-{alpha}, inhibitor of p53 transcriptional activity, prevented induction of apoptosis and activation of ERK1/2 and p38. Taken together, our data suggest that both ERK1/2 and p38 are activated in response to DBalP and that they might be involved in regulation of cellular response to DNA damage induced by DBalP, while neither kinase is involved in the release from contact inhibition induced by PAHs.},
doi = {10.1016/j.taap.2005.06.007},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 211,
place = {United States},
year = {Wed Mar 15 00:00:00 EST 2006},
month = {Wed Mar 15 00:00:00 EST 2006}
}