Drosophila von Hippel-Lindau tumor suppressor complex possesses E3 ubiquitin ligase activity

Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene predispose i ndividuals to a variety of human tumors, including renal cell carcinoma, he mangioblastoma of the central nervous system, and pheochromocytoma, Here we report on the identification and characterization of the Drosophila homolo g of VHL, The predicted amino acid sequence of Drosophila VHL protein shows 29% identity and 44% similarity to that of human VHL protein. Biochemical studies have shown that Drosophila VHL protein binds to Elongins B and C di rectly, and via this Elongin BC complex, associates with Cul-2 and Rbx1. Li ke human VHL, Drosophila MIL complex containing Cul-2, Rbx1, Elongins B and C, exhibits E3 ubiquitin ligase activity. In addition, we provide evidence that hypoxia-inducible factor (HIF)-1 alpha is the ubiquitination target o f both human and Drosophila VHL complexes. (C) 2000 Academic Press.