The DOI matches its Crossref record; 81 of the 81 references it cites were found in a registry or an index.
The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma
Open accessAbstract
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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“Inactivation of the VHL tumor suppressor gene, which results in pseudo-hypoxic stabilization of both HIF-1α and HIF-2α, is an initiating genetic event for both hereditary (VHL disease) and sporadic ccRCCs [16].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [16]
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“Although mTOR and the overall process of HIF-1α protein synthesis are limited under normoxia, it was found that 75% of sporadic clear cell RCCs are VHL-deficient, thus, in this case HIF-1α translation can proceed smoothly serving as a target for mTOR inhibitors intervention58.”
From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [58]
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Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
A conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549
Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T.-Y., Huang, L. E., Pavletich, N., Chau, V., & Kaelin, W. G. (2000) · Nature Cell Biology · doi:10.1038/35017054 · Cited by 1,577
Self-citation(2000) · PubMed · Cited by 1,445
Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. K., & Hanahan, D. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17929 · Cited by 1,361
Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene
Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., & Comoglio, P. M. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00085-0 · Cited by 1,311
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HIF-1α pathway: role, regulation and intervention for cancer therapy
Masoud, G. N., & Li, W. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2015.05.007 · Cited by 1,871
Ko, J. S., Zea, A. H., Rini, B. I., Ireland, J. L., Elson, P. J., Cohen, P. A., Golshayan, A., Rayman, P. A., Wood, L. S., García, J. A., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1332 · Cited by 861
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Targeting the ubiquitin system in cancer therapy
Hoeller, D., & Đikić, I. (2009) · Nature · doi:10.1038/nature07960 · Cited by 605
Adam, J., Hatipoglu, E., O'Flaherty, L., Ternette, N., Sahgal, N., Lockstone, H., Baban, D., Nye, E., Stamp, G. W., Wolhuter, K., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.09.006 · Cited by 585
Metadata
- Authors
- Kaelin, W. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Kaelin, William G.
- ORCID
- Kaelin, William G.
- Venue
- Clinical Cancer Research
- Published
- 2007-01-15
- Volume
- 13
- Issue
- 2
- Pages
- 680s-684s
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- 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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