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

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

doi:10.1371/journal.pbio.0000083

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 journal › Article › peer-review

454 Scopus citations

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	https://doi.org/10.1371/journal.pbio.0000083
State	Published - Jan 1 2003
Externally published	Yes

ASJC Scopus subject areas

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

Access to Document

10.1371/journal.pbio.0000083

Cite this

@article{57e23abe42c247dab248bfd6cbf25a7c,

title = "Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth",

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.",

author = "Keiichi Kondo and Kim, {William Y.} and Mirna Lechpammer and Kaelin, {William G.}",

year = "2003",

month = jan,

day = "1",

doi = "10.1371/journal.pbio.0000083",

language = "English (US)",

volume = "1",

journal = "PLoS Biology",

issn = "1544-9173",

publisher = "Public Library of Science",

number = "3",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=85027722628&partnerID=8YFLogxK

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 -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this