Background: Metformin exhibits anti-inflammatory effects. Results: In murine macrophages, metformin induces activating transcription factor-3 (ATF-3) in parallel with protective effects against LPS-induced inflammation. Conclusion: Anti-inflammatory action of metformin is at least partly mediated via ATF-3 induction. Significance: This finding provides a new perspective on metformin action and novel therapeutic means of treating inflammation-related diseases, i.e. ATF-3 modulation.

Hepatitis B virus X protein (HBx) is closely involved in the development of hepatocellular carcinoma, a highly vascularized solid tumor. Here we show that HBx increases the transcriptional activity and protein level of hypoxia-inducible factor-1alpha (HIF-1alpha) under both normoxic and hypoxic conditions, and it also stimulates angiogenesis. HBx directly interacted with the bHLH/PAS domain of HIF-1alpha but not with the von Hippel-Lindau protein (pVHL). HBx decreased the binding of pVHL to HIF-1alpha and prevented ubiquitin-dependent degradation of HIF-1alpha. In HBx-transgenic mice, HIF-1alpha and vascular endothelial growth factor were strongly detected in the dysplastic lesion, where HBx was also more highly expressed than in the non-neoplastic region of the liver. An immunohistochemical study showed that microvessels are more abundant in the dysplastic lesion than in the non-neoplastic region. Our data suggest that HBx stabilizes HIF-1alpha and leads to angiogenesis during hepatocarcinogenesis.

Hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that controls transcriptional activation of a number of genes responsive to the low cellular oxygen tension, including vascular endothelial growth factor (VEGF), erythropoietin, and glycolytic enzymes. The stability and activity of HIF-1␣ are regulated by binding to various proteins such as pVHL, p53, and p300/CBP. Here, using the yeast two-hybrid screening system, we found that HIF-1␣ interacts with Jab1 (Jun activation domain-binding protein-1), which is a coactivator of AP-1 transcription factor and fifth subunit of COP9 signalosome complex. The interaction of Jab1 with HIF-1␣ was confirmed by GST pull-down assay and also reproduced in vivo in HEK 293 cells, where endogenous Jab1 was coimmunoprecipitated with the overexpressed HIF-1␣. Moreover, Jab1-enhanced transcriptional activity of HIF-1 under hypoxia led to increase the expression of VEGF, a major HIF-1 target gene. Furthermore, Jab1 increased HIF-1␣ protein levels, which was due to the enhanced HIF-1␣ stability. The binding of HIF-1␣ and p53 tumor suppressor protein, negative regulator of HIF-1␣ stability, was interfered in a Jab1-dependent manner. Taken together, these results indicate that Jab1 should be considered as a novel regulator of HIF-1␣ stability via direct interaction.

No abstract

Mammalian aminoacyl tRNA synthetases form a macromolecular protein complex with three non-enzymatic cofactors. Among these factors, p43 is also secreted to work as a cytokine on endothelial as well as immune cells. Here we investigated the activity of p43 in angiogenesis and determined the related mediators. It promoted the migration of endothelial cells at low dose but induced their apoptosis at high dose. p43 at low concentration activated extracellular signal-regulating kinase, which resulted in the induction and activation of matrix metalloproteinase 9. In contrast, p43 at high concentration activated Jun N-terminal kinase, which mediated apoptosis of endothelial cells. These results suggest that p43 is a novel cytokine playing a dose-dependent biphasic role in angiogenesis.