Abstract
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; PKCδ and PKCe{open}) in ethanol-induced apoptosis in hepatocytes. Ethanol enhanced membrane translocation of PKCδ and PKCe{open}, which was associated with the phosphorylation of p38MAPK, p42/44MAPK and JNK1/2, and the nuclear translocation of NF-κB and AP-1. This resulted in increased apoptosis in primary rat hepatocytes. Inhibition of both PKCδ and PKCe{open} resulted in a decreased MAPK activation, decreased nuclear translocation of NF-κB and AP-1, and inhibition of apoptosis. In addition, ethanol activated the tyrosine phosphorylation of PKCδ via tyrosine kinase in hepatocytes. The tyrosine phosphorylated PKCδ was cleaved by caspase-3 and these fragments were translocated to the nucleus. Inhibition of ethanol-induced oxidative stress blocked the membrane translocation of PKCδ and PKCe{open}, and the tyrosine phosphorylation of PKCδ in hepatocytes. Inhibition of oxidative stress, tyrosine kinase or caspase-3 activity caused a decreased nuclear translocation of PKCδ 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.
Original language | English (US) |
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Pages (from-to) | 2339-2350 |
Number of pages | 12 |
Journal | Cellular Signalling |
Volume | 19 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2007 |
Keywords
- Apoptosis
- Mitogen-activated protein kinase
- Oxidative stress
- Phosphorylation
- Primary rat hepatocytes
- Protein kinase C
- Translocation
ASJC Scopus subject areas
- Cell Biology