Germ line inactivation of the von-Hippel-Lindau (VHL) tumor suppressor gene 
causes von Hippel-Lindau hereditary cancer syndrome, and somatic mutations of 
this gene have been linked to the development of sporadic hemangioblastomas and 
clear cell renal carcinomas. The protein encoded by VHL, pVHL, has no known 
enzymatic activities but interacts with various partner proteins. In this 
review, various pVHL functions are highlighted. pVHL acts as a multi-purpose 
adaptor protein that controls different gene expression programs. Through its 
oxygen-dependent regulation of hypoxia-inducible factor alpha (HIFalpha), pVHL 
plays a central role in the oxygen-sensing pathway. In addition, many 
HIFalpha-independent functions of pVHL have recently been identified. These 
include microtubule-based processes, extracellular matrix assembly and 
suppression of kidney cyst formation. These complex pVHL functions can explain 
the diverse consequences of pVHL dysregulation in tumor formation and 
progression.