Journal
CELLULAR SIGNALLING
Volume 19, Issue 11, Pages 2339-2350Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2007.07.013
Keywords
primary rat hepatocytes; oxidative stress; protein kinase C; mitogen-activated protein kinase; phosphorylation; translocation; apoptosis
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Funding
- NIAAA NIH HHS [AA006386] Funding Source: Medline
- NIDDK NIH HHS [DK069939] Funding Source: Medline
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Ethanol abuse is one of the major etiologies of cirrhosis. Ethanol has been shown to induce apoptosis via activation of oxidative stress, mitogen-activated protein kinases (MAPK), and tyrosine kinases. However, there is a paucity of data that examine the interplay among these molecules. In the present study we have systematically elucidated the role of novel protein kinase C isofomis (nPKC; PKC delta and PKC epsilon) in ethanol-induced apoptosis in hepatocytes. Ethanol enhanced membrane translocation of PKC delta and PKC epsilon, which was associated with the phosphorylation of p38MAPK, p42/44MAPK and JNK1/2, and the nuclear translocation of NF-kappa B and AP-1. This resulted in increased apoptosis in primary rat hepatocytes. Inhibition of both PKC delta and PKC epsilon resulted in a decreased MAPK activation, decreased nuclear translocation of NF-kappa B nd AP-1, and inhibition of apoptosis. In addition, ethanol activated the tyrosine phosphorylation of PKC delta via tyrosine kinase in hepatocytes. The tyrosine phosphorylated PKC delta was cleaved by caspase-3 and these fragments were translocated to the nucleus. Inhibition of ethanol-induced oxidative stress blocked the membrane translocation of PKC delta and PKC epsilon, and the tyrosine phosphorylation of PKC delta in hepatocytes. Inhibition of oxidative stress, tyrosine kinase or caspase-3 activity caused a decreased nuclear translocation of PKC delta in response to ethanol, and was associated with less apoptosis. Conclusion: These results provide a newly-described mechanism by which ethanol induces apoptosis via activation of nPKC isoforms in hepatocytes. (C) 2007 Elsevier Inc. All rights reserved.
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