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

Abstract

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.

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway

“…In support of a functional relationship between VHL and JAB1, the latter could be co-immunoprecipitated with VHL in WT8 cells. Importantly, recent data suggest a further connection between JAB1 and VHL through HIF-1a (Bae et al, 2002). These investigators reported direct binding between JAB1 and HIF1a, a ecting the stability of the latter under hypoxic conditions.…”

Jab1 is overexpressed in human breast cancer and is a downstream target for HER-2/neu

“…Jab1 also binds hypoxia inducible factor-1, prevents its degradation and enhances its transcriptional activity. 28 Upregulation Figure 2 Increase of Jab1 expression in HER-2/neu-overexpressing human breast cancer cells. (a) MCF-7 (MCF) and MDA-MB-453 (453) human breast cancer cells cultured in 10% fetal calf serum medium.…”

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

“…Consequently, the HIF-1 protein is stabilized and translocated into the nucleus [19], where it binds to HREs to regulate expression of its target genes ( Figure 2). In addition to VHL, murine double minute 2 [30] and Jab1 [31] have also been reported to affect the ubiquitination and stability of HIF-1. It should be pointed out that the protein stability and transcriptional activity of HIF-1 can be regulated by several other factors besides hypoxia, such as the accumulation of intermediate metabolites, the loss of tumor-suppressor function and the gain of oncogene function [32].…”