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 language | English (US) |
|---|---|
| Journal | PLoS Biology |
| Volume | 1 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jan 1 2003 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth
AU - Kondo, Keiichi
AU - Kim, William Y.
AU - Lechpammer, Mirna
AU - Kaelin, William G.
PY - 2003/1/1
Y1 - 2003/1/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85027722628&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.0000083
DO - 10.1371/journal.pbio.0000083
M3 - Article
C2 - 14691554
AN - SCOPUS:2342597973
VL - 1
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 3
ER -