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

By M. Bae, M. Ahn, Joo-Won Jeong, M. Bae, Y. M. Lee, S. Bae, Jong-Wan Park, Kwang-Rok Kim, Kyu-Won Kim. Journal of Biological Chemistry, 2002

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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-1α 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-1α 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-1α 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-1α. 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-1α protein levels, which was due to the enhanced HIF-1α stability. The binding of HIF-1α and p53 tumor suppressor protein, negative regulator of HIF-1α stability, was interfered in a Jab1-dependent manner. Taken together, these results indicate that Jab1 should be considered as a novel regulator of HIF-1α stability via direct interaction.

Subfields: Cancer Research, Molecular Biology

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