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J. Biol. Chem. 277 (42): 39887-39898

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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

Mina I. ZhouDagger , Hongmei WangDagger , Jonathan J. Ross§, Igor Kuzmin, Chengen XuDagger , and Herbert T. CohenDagger §||

From the Departments of Dagger  Medicine and § Pathology, Sections of Nephrology and Hematology/Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118 and  NCI, National Institutes of Health, Frederick Cancer Research Center, Frederick, Maryland 21702

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 (gene for Apoptosis and Differentiation in Epithelia) 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.

* This work was supported by the National Institutes of Health Grants T32-DK07053 and F32-CA79133 (to M. Z.) and R01-CA79830 (to H. T. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF520952.

|| To whom correspondence should be addressed: Evans Biomedical Research Center, X-535, Boston University Medical Center, 650 Albany St., Boston, MA 02118. Tel.: 617-638-7322; Fax: 617-638-7326; E-mail: htcohen@bu.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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