Abstract
Jade-1 was identified as a protein partner of the von Hippel-Lindau tumor suppressor pVHL. The interaction of Jade-1 and pVHL correlates with renal cancer risk. We have investigated the molecular function of Jade-1. Jade-1 has two zinc finger motifs called plant homeodomains (PHD). A line of evidence suggests that the PHD finger functions in chromatin remodeling and protein-protein interactions. We determined the cellular localization of Jade-1 and examined whether Jade-1 might have transcriptional and histone acetyltransferase (HAT) functions. Biochemical cell fractionation studies as well as confocal images of cells immunostained with a specific Jade-1 antibody revealed that endogenous Jade-1 is localized predominantly in the cell nucleus. Tethering of Gal4-Jade-1 fusion protein to Gal4-responsive promoters in co-transfection experiments activated transcription 5-6-fold, indicating that Jade-1 is a possible transcriptional activator. It was remarkable that overexpression of Jade-1 in cultured cells specifically increased levels of endogenous acetylated histone H4, but not histone H3, strongly suggesting that Jade-1 associates with HAT activity specific for histone H4. Deletion of the two PHD fingers completely abolished Jade-1 transcriptional and HAT activities, indicating that these domains are indispensable for Jade-1 nuclear functions. In addition, we demonstrated that TIP60, a known HAT with histone H4/H2A specificity, physically associates with Jade-1 and is able to augment Jade-1 HAT function in live cells, strongly suggesting that TIP60 might mediate Jade-1 HAT activity. Thus, Jade-1 is a novel candidate transcriptional co-activator associated with HAT activity and may play a key role in the pathogenesis of renal cancer and von Hippel-Lindau disease.
Highlights
The von Hippel-Lindau (VHL)1 disease gene VHL is the major renal cancer gene in adults
Jade-1-associated histone acetyltransferase (HAT) Activity Requires plant homeodomains (PHD) Zinc Finger— Because deletion of the PHD fingers knocked out Jade-1 transcriptional function, we examined whether the PHD fingers are essential for Jade-1-associated HAT activity
Overexpression of Jade-1d lacking only the second PHD finger resulted in reduced levels of H4 acetylation (Fig. 5B, lane 4), indicating that this specific domain composed of 61 aa residues is required for full Jade-1-associated HAT activity
Summary
The von Hippel-Lindau (VHL)1 disease gene VHL is the major renal cancer gene in adults. Overexpression of Jade-1d lacking only the second PHD finger resulted in reduced levels of H4 acetylation (Fig. 5B, lane 4), indicating that this specific domain composed of 61 aa residues is required for full Jade-1-associated HAT activity.
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