The von Hippel-Lindau Tumor Suppressor Stabilizes Novel Plant Homeodomain Protein Jade-1

• Published in: The Journal of biological chemistry 2002-10, Vol.277 (42), p.39887-39898
• Main Authors: Zhou, Mina I, Wang, Hongmei, Ross, Jonathan J, Kuzmin, Igor, Xu, Chengen, Cohen, Herbert T
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Blotting, Northern; Blotting, Western; Cell Nucleus - metabolism; Cytoplasm - metabolism; Gene Library; Homeodomain Proteins - chemistry; Homeodomain Proteins - physiology; Humans; Immunohistochemistry; Kidney - metabolism; Ligases - metabolism; Ligases - physiology; Microscopy, Fluorescence; Molecular Sequence Data; Plasmids - metabolism; Precipitin Tests; Protein Binding; Protein Structure, Tertiary; Time Factors; Tissue Distribution; Transfection; Tumor Suppressor Proteins; Two-Hybrid System Techniques; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M205040200

The von Hippel-Lindau disease gene ( VHL ) is the causative gene for most adult renal cancers. However, the mechanism by which VHL protein functions as a renal tumor suppressor remains largely unknown. To identify low occupancy VHL protein partners with potential relevance to renal cancer, we screened a human kidney library against human VHL p30 using a yeast two-hybrid approach. Jade-1 ( g ene for A poptosis and D ifferentiation in E pithelia) encodes a previously uncharacterized 64-kDa protein that interacts strongly with VHL protein and is most highly expressed in kidney. Jade-1 protein is short-lived and contains a candidate destabilizing (PEST) motif and plant homeodomains that are not required for the VHL interaction. Jade-1 is abundant in proximal tubule cells, which are clear-cell renal cancer precursors, and expression increases with differentiation. Jade-1 is expressed in cytoplasm and the nucleus diffusely and in speckles, where it partly colocalizes with VHL. VHL reintroduction into renal cancer cells increases endogenous Jade-1 protein abundance up to 10-fold. Furthermore, VHL increases Jade-1 protein half-life up to 3-fold. Thus, direct protein stabilization is identified as a new VHL function. Moreover, Jade-1 protein represents a novel candidate regulatory factor in VHL-mediated renal tumor suppression.