Jab1 interacts directly with HIF-1alpha 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-1alpha 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-1alpha 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-1alpha 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-1alpha. 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-1alpha protein levels, which was due to the enhanced HIF-1alpha stability. The binding of HIF-1alpha and p53 tumor suppressor protein, negative regulator of HIF-1alpha stability, was interfered in a Jab1-dependent manner. Taken together, these results indicate that Jab1 should be considered as a novel regulator of HIF-1alpha stability via direct interaction.
Bae
Moon-Kyoung
MK
Department of Molecular Biology, Pusan National University, Pusan 609-735, Korea.
Ahn
Mee-Young
MY
Jeong
Joo-Won
JW
Bae
Myung-Ho
MH
Lee
You Mie
YM
Bae
Soo-Kyung
SK
Park
Jong-Wan
JW
Kim
Kwang-Rok
KR
Kim
Kyu-Won
KW
D001667:Binding, Competitive; D000075686:COP9 Signalosome Complex; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D010447:Peptide Hydrolases; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex