Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth.

Keiichi Kondo,Mirna Lechpammer,William Y Kim,William G Kaelin,Christopher Kemp Christopher Kemp

doi:10.1371/journal.pbio.0000083

Abstract

Biallelic inactivation of the von Hippel–Lindau tumor suppressor gene (VHL) is linked to the development of hereditary (VHL-associated) and sporadic clear-cell renal carcinomas as well as other abnormalities. The VHL gene product, pVHL, is part of an E3 ubiquitin ligase complex that targets the α subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for degradation in the presence of oxygen. Here we report that a HIF2α variant lacking both of its two prolyl hydroxylation/pVHL-binding sites prevents tumor inhibition by pVHL in a DNA-binding dependent manner. Conversely, downregulation of HIF2α with short hairpin RNAs is sufficient to suppress tumor formation by pVHL-defective renal carcinoma cells. These results establish that tumor suppression by pVHL is linked to regulation of HIF target genes.

Highlights

Introduction von HippelLindau (VHL) disease is caused by heterozygous germline inactivation of the von Hippel–Lindau tumor suppressor gene (VHL) tumor suppressor gene, which resides on chromosome 3p25 (Kaelin 2002)
In this report we provide data that strengthen our earlier conclusion that inhibition of HIF2a is necessary for pVHLdependent suppression of renal carcinoma tumor formation in vivo (Kondo et al 2002)
We previously showed that a HIF2a variant in which Pro531 was replaced by alanine (HIF2a P531A) escaped recognition by VHL gene product (pVHL) and induced the expression of hypoxia-inducible factor (HIF) target genes in vivo (Kondo et al 2002)

Summary

Introduction

Introduction von HippelLindau (VHL) disease is caused by heterozygous germline inactivation of the VHL tumor suppressor gene, which resides on chromosome 3p25 (Kaelin 2002). Restoration of pVHL function is sufficient to suppress tumor formation by pVHL-defective renal carcinoma cells in vivo (Iliopoulos et al 1995; Gnarra et al 1996; Schoenfeld et al 1998).

Results

Conclusion