Jab1 Interacts Directly with HIF-1 and Regulates Its Stability*

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 HIF1 . 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.