Inhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth
Copyright policy )Inhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth
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 alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for degradation in the presence of oxygen. Here we report that a HIF2alpha 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 HIF2alpha 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.
- Harvard University United States
- Dana-Farber Cancer Institute United States
- Howard Hughes Medical Institute United States
- Woman's Hospital United States
- Harvard Medical School United States
QH301-705.5, Immunoblotting, Molecular Sequence Data, Down-Regulation, Mice, Nude, Mice, Cell Line, Tumor, Basic Helix-Loop-Helix Transcription Factors, Animals, Humans, Gene Silencing, Biology (General), Alleles, Cell Proliferation, Binding Sites, Base Sequence, Genetic Variation, Kidney Neoplasms, Gene Expression Regulation, Neoplastic, Dimerization, Neoplasm Transplantation, Research Article, Adenocarcinoma, Clear Cell
QH301-705.5, Immunoblotting, Molecular Sequence Data, Down-Regulation, Mice, Nude, Mice, Cell Line, Tumor, Basic Helix-Loop-Helix Transcription Factors, Animals, Humans, Gene Silencing, Biology (General), Alleles, Cell Proliferation, Binding Sites, Base Sequence, Genetic Variation, Kidney Neoplasms, Gene Expression Regulation, Neoplastic, Dimerization, Neoplasm Transplantation, Research Article, Adenocarcinoma, Clear Cell
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