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Zhang, Y, Venugopal, SK, He, S, Liu, P, Wu, J and Zern, MA (2007) Ethanol induces apoptosis in hepatocytes by a pathway involving novel protein kinase C isoforms. Cell. Signal. 19:2339-50


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 isoforms (nPKC; PKCdelta and PKCepsilon) in ethanol-induced apoptosis in hepatocytes. Ethanol enhanced membrane translocation of PKCdelta and PKCepsilon, which was associated with the phosphorylation of p38MAPK, p42/44MAPK and JNK1/2, and the nuclear translocation of NF-kappaB and AP-1. This resulted in increased apoptosis in primary rat hepatocytes. Inhibition of both PKCdelta and PKCepsilon resulted in a decreased MAPK activation, decreased nuclear translocation of NF-kappaB and AP-1, and inhibition of apoptosis. In addition, ethanol activated the tyrosine phosphorylation of PKCdelta via tyrosine kinase in hepatocytes. The tyrosine phosphorylated PKCdelta was cleaved by caspase-3 and these fragments were translocated to the nucleus. Inhibition of ethanol-induced oxidative stress blocked the membrane translocation of PKCdelta and PKCepsilon, and the tyrosine phosphorylation of PKCdelta in hepatocytes. Inhibition of oxidative stress, tyrosine kinase or caspase-3 activity caused a decreased nuclear translocation of PKCdelta 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.


PubMed Online version:10.1016/j.cellsig.2007.07.013


Animals; Apoptosis/drug effects; Caspase 3/metabolism; Cell Membrane/drug effects; Cell Membrane/enzymology; Cells, Cultured; Enzyme Activation/drug effects; Ethanol/pharmacology; Fluoresceins/pharmacology; Hepatocytes/cytology; Hepatocytes/drug effects; Hepatocytes/enzymology; Isoenzymes/antagonists & inhibitors; Isoenzymes/metabolism; Male; Metalloporphyrins/pharmacology; Mitogen-Activated Protein Kinases/metabolism; Polyethylene Glycols/pharmacology; Protein Kinase C-delta/antagonists & inhibitors; Protein Kinase C-delta/metabolism; Protein Kinase C-epsilon/antagonists & inhibitors; Protein Kinase C-epsilon/metabolism; Protein Kinase Inhibitors/pharmacology; Protein Processing, Post-Translational/drug effects; Protein Transport/drug effects; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species/metabolism; Superoxide Dismutase/pharmacology



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status



GO:0045471: response to ethanol

ECO:0000270: expression pattern evidence used in manual assertion


Seeded From UniProt


See also


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