Von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF

Michael A. Hoffman, Michael Ohh, Haifeng Yang, Jeff M. Klco, Mircea Ivan, William G. Kaelin

Research output: Contribution to journalArticle

304 Scopus citations


von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germ line mutation of the von Hippel-Lindau tumor suppressor gene (VHL). Tumors observed in this disorder include retinal and central nervous system hemangioblastomas, clear cell renal carcinomas and pheochromocytomas. The VHL gene product, pVHL, is a component of a ubiquitin ligase which targets the transcription factor known as hypoxia-inducible factor (HIF) for degradation in the presence of oxygen. pVHL also plays roles in the control of extracellular matrix formation and cell-cycle exit. Different VHL mutations confer different site-specific risks of cancer. Type 2C VHL mutations confer an increased risk of pheochromocytoma without the other stigmata of VHL disease. Here we report that the products of such type 2C VHL alleles retain the ability to down regulate HIF but are defective for promotion of fibronectin matrix assembly. Furthermore, pVHL L188V, a well studied type 2C mutant, retained the ability to suppress renal carcinoma growth in vivo. These studies strengthen the notion that HIF deregulation plays a causal role in hemangioblastoma and renal carcinoma, and raises the possibility that abnormal fibronectin matrix assembly contributes to pheochromocytoma pathogenesis in the setting of VHL disease.

Original languageEnglish (US)
Pages (from-to)1019-1027
Number of pages9
JournalHuman molecular genetics
Issue number10
StatePublished - May 1 2001
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF'. Together they form a unique fingerprint.

  • Cite this