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) |
|---|---|
| Pages (from-to) | 2339-2350 |
| Number of pages | 12 |
| Journal | Cellular Signalling |
| Volume | 19 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2007 |
Fingerprint
Keywords
- Apoptosis
- Mitogen-activated protein kinase
- Oxidative stress
- Phosphorylation
- Primary rat hepatocytes
- Protein kinase C
- Translocation
ASJC Scopus subject areas
- Cell Biology
Cite this
Ethanol induces apoptosis in hepatocytes by a pathway involving novel protein kinase C isoforms. / Zhang, Yanhong; Venugopal, Senthil K.; He, Songqing; Liu, Pingguo; Wu, Jian; Zern, Mark A.
In: Cellular Signalling, Vol. 19, No. 11, 11.2007, p. 2339-2350.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ethanol induces apoptosis in hepatocytes by a pathway involving novel protein kinase C isoforms
AU - Zhang, Yanhong
AU - Venugopal, Senthil K.
AU - He, Songqing
AU - Liu, Pingguo
AU - Wu, Jian
AU - Zern, Mark A
PY - 2007/11
Y1 - 2007/11
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Mitogen-activated protein kinase
KW - Oxidative stress
KW - Phosphorylation
KW - Primary rat hepatocytes
KW - Protein kinase C
KW - Translocation
UR - http://www.scopus.com/inward/record.url?scp=34548402471&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548402471&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2007.07.013
DO - 10.1016/j.cellsig.2007.07.013
M3 - Article
C2 - 17728104
AN - SCOPUS:34548402471
VL - 19
SP - 2339
EP - 2350
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
IS - 11
ER -