AMPK activation modulates JNK-NF-κB signaling cascade during hypoxia and reoxygenation stress conditions. Cardiac AMPK activation plays a critical role in maintaining mitochondrial function and inhibiting the inflammatory response caused by ischemic insults.
Hepatitis C virus nonstructural protein 4B (NS4B) is an endoplasmic reticulum (ER) membrane associated protein and a potent causative factor of ER stress. Here we reported that unfolded protein response (UPR) can be activated by HCV NS4B through inducing both XBP1 mRNA splicing and ATF6 cleavage in human hepatic cells. Flow cytometric analysis revealed that HCV NS4B stimulates the production of reactive oxygen species (ROS) by perturbing intracellular Ca(2+) homeostasis. Luciferase assay showed that HCV NS4B also activates the multifunctional transcription factor, NF-kappaB, in a dose-dependent manner through Ca(2+) signaling and ROS. Further immunoblot analysis showed that HCV NS4B promotes NF-kappaB translocation into the nucleus via protein-tyrosine kinase (PTK) mediated phosphorylation and subsequent degradation of IkappaBalpha. These studies provide an important insight into the implication of NS4B in HCV life cycle and HCV-associated liver disease by affecting host intracellular signal transduction pathways.
Significance
Epigenetic changes commonly occur in hepatocellular carcinoma (HCC) and are associated with aberrant gene expression. Most studies have focused on epigenetic gene-silencing events; therefore, the mechanism that promotes gene activation in HCC is not well established. We identify an epigenetic activation mechanism whereby menin promotes Yes-associated protein (Yap1) transcription, which is associated with a poor prognosis for HCC patients. Substantial overexpression of the menin–mixed-lineage leukemia complex is associated with increased histone 3 lysine 4 trimethylation at certain loci of the tumor promoter in HCC. Heterozygous ablation of multiple endocrine neoplasia type 1 (
Men1)
in mice reduces diethylnitrosamine-induced development of HCC. Our findings reveal that menin plays an important epigenetic role in up-regulating Yap1 transcription, leading to liver tumorigenesis.
In patients with NPC, rAd-p53 was safe and biologically active. Our results indicated that rAd-p53 improves radiotherapeutic tumor control and survival rate in patients with NPC.
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