The von Hippel–Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-α transcription factors1; additional mechanisms have been proposed2. pVHL also stabilizes the plant homeodomain protein Jade-1, which is a candidate renal tumour suppressor that may correlate with renal cancer risk3,4,5. Here we show that Jade-1 binds the oncoprotein β-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild-type β-catenin but not a cancer-causing form of β-catenin. Whereas the well-established β-catenin E3 ubiquitin ligase component β-TrCP ubiquitylates only phosphorylated β-catenin6, Jade-1 ubiquitylates both phosphorylated and non-phosphorylated β-catenin and therefore regulates canonical Wnt signalling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of β-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL downregulates β-catenin in a Jade-1-dependent manner and inhibits Wnt signalling, supporting a role for Jade-1 and Wnt signalling in renal tumorigenesis. The pVHL tumour suppressor and the Wnt tumorigenesis pathway are therefore directly linked through Jade-1.
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We thank Z.-X. Xiao (Boston University) for insightful suggestions and careful review of the manuscript; K. Symes, M. Malikova and E. Smith (all of Boston University) for Xenopus laevis embryos; R. Kemler (Max Planck Institute for Immunobiology, Germany) for providing the β-catenin S33A construct; W. Birchmeier (Max Delbruck Center for Molecular Medicine, Germany) for β-catenin C and N terminus deletion constructs; and R. Benarous (Institute Pasteur, France) for wild-type and DN β-TrCP in pcDNA3.1 Myc/His vector. This work was supported by fellowship grants from the National Kidney Foundation and Polycystic Kidney Disease Foundation (to V.C.C.) and by National Institutes of Health (NIH) Training Grant T32 DK07053 (for V.C.C. and R.L.F.); by American Heart Association grant SDG 0535485T and American Cancer Society grant IRG-72-001-32-IRG (to M.V.P.); by a pilot research grant from the Department of Medicine at Boston University School of Medicine and a Karin Grunebaum Junior Faculty Cancer Research Award (to I.D.); and by NIH grants R01 CA71796 (to D.C.S.) and R01 CA79830 and R01 DK67569 (to H.T.C.). Part of this work was presented at the American Society of Nephrology annual meeting in San Diego, California, USA, in November 2006, and at the American Society of Nephrology annual meeting in San Francisco, California, USA, in November 2007.