Inhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth

• DOI: 10.1371/journal.pbio.0000083
• Publication Date: 2003-12-22T06:54:24Z
• Authors: Keiichi Kondo; William Y Kim; Mirna Lechpammer; William G Kaelin
• Keywords: Hypoxia-Inducible Factors; Ubiquitin-Protein Ligases; HEK 293 cells

Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene (VHL) is linked to development hereditary (VHL-associated) and sporadic clear-cell renal carcinomas as well other abnormalities. The VHL product, pVHL, part an E3 ubiquitin ligase complex that targets alpha subunits heterodimeric transcription factor HIF (hypoxia-inducible factor) for degradation in presence oxygen. Here we report a HIF2alpha variant lacking both its two prolyl hydroxylation/pVHL-binding sites prevents inhibition by pVHL DNA-binding dependent manner. Conversely, downregulation with short hairpin RNAs sufficient suppress formation pVHL-defective carcinoma cells. These results establish suppression regulation target genes.