The dual roles of c-Jun NH2-terminal kinase signaling in Cr(VI)-induced apoptosis in JB6 cells.
Occupational exposure to chromium (Cr) compounds has been shown to cause serious toxic and carcinogenic effects. The skin is an important target for the compounds in industrially exposed Cr workers. c-Jun NH(2)-terminal kinase (JNK) regulates cell proliferation, apoptosis, and differentiation. This protein's effects on cellular response depend upon the cell type and stimuli. The mechanisms by which hexavalent chromium (Cr(VI)) leads to apoptosis in the skin are unclear at present. The aim of this study is to examine whether JNK regulates apoptosis in Cr(VI)-exposed mouse JB6 epidermal cells. The present study showed that Cr(VI) induced apoptotic cell death through JNK activation. The blockage of JNK by small interference RNA (si-RNA) transfection suppressed Cr(VI)-induced apoptotic cell death with the concomitant downregulation of antiapoptotic Bcl-2 family proteins, mitochondrial membrane depolarization (Δψm), caspase activation, and poly (ADP-ribose) polymerase cleavage. However, inhibition of c-Jun expression by si-RNA transfection enhanced cytotoxicity, which corresponded to increasing apoptosis and Δψm. This phenomenon is associated with p53 activation caused by increasing reactive oxygen species (ROS) levels because of the downregulation of superoxide dismutase expression in si-c-Jun-transfected cells. Taken together, Cr(VI) induces apoptosis via JNK-mediated signaling, whereas c-Jun activation acts as an inhibitor of apoptotic signaling. Additionally, ROS generated by Cr(VI) is a pivotal regulator of JNK.
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305, USA.
Young-Ok
YO
Son
John Andrew
JA
Hitron
Senping
S
Cheng
Amit
A
Budhraja
Zhuo
Z
Zhang
Nancy
N
Lan Guo
Jeong-Chae
JC
Lee
Xianglin
X
Shi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D002857:Chromium / Q000633:toxicity*; D004578:Electron Spin Resonance Spectroscopy; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
D017382:Reactive Oxygen Species; D002857:Chromium; D013481:Superoxides; D048031:JNK Mitogen-Activated Protein Kinases