Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth

Keiichi Kondo, William Y. Kim, Mirna Lechpammer, William G. Kaelin

Research output: Contribution to journalArticle

413 Citations (Scopus)

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 a 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.

Original languageEnglish (US)
JournalPLoS Biology
Volume1
Issue number3
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

Fingerprint

Tumors
Renal Cell Carcinoma
neoplasms
carcinoma
Genes
hypoxia
Growth
Neoplasms
ubiquitin-protein ligase
tumor suppressor genes
Ubiquitin-Protein Ligases
hydroxylation
Hydroxylation
kidney cells
small interfering RNA
Tumor Suppressor Genes
Small Interfering RNA
binding sites
inactivation
Transcription Factors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. / Kondo, Keiichi; Kim, William Y.; Lechpammer, Mirna; Kaelin, William G.

In: PLoS Biology, Vol. 1, No. 3, 01.01.2003.

Research output: Contribution to journalArticle

Kondo, Keiichi ; Kim, William Y. ; Lechpammer, Mirna ; Kaelin, William G. / Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. In: PLoS Biology. 2003 ; Vol. 1, No. 3.
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