Focus of Research:
Co-Authors Vipul C. Chitalia, Rebecca L. Foy, Markus M. Bachschmid, Liling Zeng, Maria V. Panchenko, Mina I. Zhou, Ajit Bharti, David C. Seldin, Stewart H. Lecker, Isabel Dominguez and Herbert T. Cohen
The von Hippel–Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-α transcription factors; additional mechanisms have been proposed. pVHL also stabilizes the plant homeodomain protein Jade-1, which is a candidate renal tumour suppressor that may correlate with renal cancer risk. Here we show that Jade-1 binds the oncoprotein &live;-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild- type &live;-catenin but not a cancer-causing form of &live;-catenin. Whereas the well-established &live;-catenin E3 ubiquitin ligase component &live;-TrCP ubiquitylates only phosphorylated &live;-catenin, Jade-1 ubiquitylates both phosphorylated and non-phosphorylated &live;-catenin and therefore regulates canonical Wnt signalling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of &live;-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL downregulates &live;-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.
Nat Cell Biol. 2008; 10(10):1208-16