Skip Navigation



ToxSci Advance Access published online on July 14, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh221
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
81/2/518    most recent
kfh221v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Kim, J.
Right arrow Articles by Sharma, R. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kim, J.
Right arrow Articles by Sharma, R. P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received May 11, 2004
Accepted July 2, 2004

Systems Evaluation

Calcium-Mediated Activation of c-Jun NH2-Terminal Kinase (JNK) and Apoptosis in Response to Cadmium in Murine Macrophages

Jiyoung Kim 1 Raghubir P. Sharma 1*

1 Interdisciplinary Program of Toxicology, Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia, USA 30602-7389

* To whom correspondence should be addressed. E-mail: rpsharma{at}vet.uga.edu.


  Abstract

Cadmium is a well-known carcinogenic and immunotoxic metal commonly found in cigarette smoke and industrial effluent. Altered intracellular calcium ([Ca2+]i) level has been implicated in the pathophysiology of immune dysfunction. Present study was designed to determine the possible involvement of calcium (Ca2+) and mitogen-activated protein kinases (MAPKs) signaling pathways on cadmium-induced cell death in J774A.1 murine macrophage cells. Cadmium caused a low amplitude [Ca2+]i elevation at 20 µM and rapid and high amplitude [Ca2+]i elevation at 500 µM. Exposure to cadmium dose-dependently induced phosphorylation of c-Jun NH2-terminal kinase (JNK) and deactivated p38 MAPK. Use of selective JNK inhibitor, SP600125, suggested that activation of JNK is pro-apoptotic and pro-necrotic. Buffering of the calcium response with 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxy-methyl) ester (BAPTA-AM) and ethylene glycol-bis-({beta}-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) completely blocked cadmium-induced apoptotic response. The pretreatment of cells with BAPTA-AM and EGTA suppressed the cadmium-induced cell injury including growth arrest, mitochondrial activity impairment and necrosis as well as recovered the cadmium-altered JNK and p38 MAPK activity. Chelating [Ca2+]i also reversed cadmium-induced hydrogen peroxide generation suggesting that production of reactive oxygen species (ROS) is related to [Ca2+]i. The present study showed that cadmium induces ROS-[Ca2+]i-JNK-caspase-3 signaling pathway leading to apoptosis. Furthermore, cadmium-induced [Ca2+]i regulates phosphorylation/dephosphorylation of JNK and p38, and modulates signal transduction pathways to proliferation, mitochondrial activity and necrosis.

Keywords: cadmium; calcium; ROS; MAPKs; growth arrest; apoptosis.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
S. Wang, M. Tang, B. Pei, X. Xiao, J. Wang, H. Hang, and L. Wu
Cadmium-Induced Germline Apoptosis in Caenorhabditis elegans: The Roles of HUS1, p53, and MAPK Signaling Pathways
Toxicol. Sci., April 1, 2008; 102(2): 345 - 351.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
Y. Nakatsu, Y. Kotake, and S. Ohta
Concentration Dependence of the Mechanisms of Tributyltin-Induced Apoptosis
Toxicol. Sci., June 1, 2007; 97(2): 438 - 447.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
M. Nawaz, C. Manzl, V. Lacher, and G. Krumschnabel
Copper-Induced Stimulation of Extracellular Signal-Regulated Kinase in Trout Hepatocytes: The Role of Reactive Oxygen Species, Ca2+, and Cell Energetics and the Impact of Extracellular Signal-Regulated Kinase Signaling on Apoptosis and Necrosis
Toxicol. Sci., August 1, 2006; 92(2): 464 - 475.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
L. Aimo and P. I. Oteiza
Zinc Deficiency Increases the Susceptibility of Human Neuroblastoma Cells to Lead-Induced Activator Protein-1 Activation
Toxicol. Sci., May 1, 2006; 91(1): 184 - 191.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.