Cited by 336Renal cell carcinoma treatmentCancer, Hypoxia, and MetabolismAngiogenesis and VEGF in Cancer

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The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma

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Kaelin, William G.·2007·Clinical Cancer Research

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Abstract

Germ line VHL tumor suppressor gene loss-of-function mutations cause von Hippel-Lindau disease, which is associated with an increased risk of central nervous system hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas. Somatic VHL mutations are also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the α-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitylation, and hence, proteasomal degradation, when oxygen is available. pVHL-defective clear cell renal carcinomas overproduce a variety of mRNAs that are under the control of HIF, including the mRNAs that encode vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor α. In preclinical models, down-regulation of HIF-α, especially HIF-2α, is both necessary and sufficient for renal tumor suppression by pVHL. These observations are probably relevant to the demonstrated clinical activity of vascular endothelial growth factor antagonists in clear cell renal carcinoma and form a foundation for the testing of additional agents that inhibit HIF, or HIF-responsive gene products, in this disease.

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Authors: Kaelin, W. G.
Affiliations: Brigham and Women's Hospital (US)
Corresponding author: Kaelin, William G.
ORCID: Kaelin, William G.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2007-01-15
Volume: 13
Issue: 2
Pages: 680s-684s
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-06-1865
OpenAlex: W2131473358
Semantic Scholar: b1ecaaf13be1baca02f75edb325c7d80e991f9a6
Cited by: 336
References: 80
Citations by year: 2026: 13 · 2025: 13 · 2024: 6 · 2023: 9 · 2022: 11 · 2021: 11 · 2020: 9 · 2019: 9 · 2018: 14 · 2017: 13 · 2016: 14 · 2015: 14 · 2014: 18 · 2013: 18 · 2012: 28
FWCI: 5.33
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords: von Hippel-Lindau protein, VHL tumor suppressor, clear cell renal cell carcinoma, hypoxia-inducible factor, HIF-2α, HIF-1α, ubiquitin ligase, vascular endothelial growth factor, platelet-derived growth factor B, transforming growth factor-alpha, VEGF inhibitors, von Hippel-Lindau disease
MeSH terms: Carcinoma, Renal Cell, Genotype, Humans, Kidney Neoplasms, Mutation, RNA, Messenger, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Dimerization, Vascular Endothelial Growth Factor A, Von Hippel-Lindau Tumor Suppressor Protein

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The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma

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