Health Dictionary
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Von Hippel-Lindau tumor suppressor
Introduction
Overview
Overview
The Von Hippel-Lindau tumor suppressor protein is a protein whose inactivation is associated with Von Hippel-Lindau disease.
Von Hippel-Lindau syndrome (VHL) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign tumors of the eye, brain, spinal cord, kidney, pancreas, and adrenal glands. A germline mutation of this gene is the basis of familial inheritance of VHL syndrome. The protein encoded by this gene is a component of the protein complex that includes elongin B, elongin C, and cullin-2, and possesses ubiquitin ligase E3 activity. This protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. RNA polymerase II subunit POLR2G/RPB7 is also reported to be a target of this protein. Alternatively spliced transcript variants encoding distinct isoforms have been observed.[1]
The disease is caused by mutations of the VHL gene on the short arm of the third chromosome (3p26-p25).
Function
Function
The resultant protein is produced in two forms, an 18 kDa and a 30 kDa protein that functions as a tumor suppressor gene. The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being ‘marked’ for degradation.
The most researched of these targets is hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors. (However, VHL does play other roles in tumor regulation.)[2]
Pathology
Pathology
It stands to reason that the loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of angiogenic factors, including VEGF and PDGF. In turn, this leads to unregulated blood vessel growth, one of the prerequisites of a tumour.
References
References
- ↑ “Entrez Gene: VHL von Hippel-Lindau tumor suppressor”.
- ↑ Czyzyk-Krzeska MF, Meller J (2004). “von Hippel-Lindau tumor suppressor: not only HIF’s executioner”. Trends in molecular medicine. 10 (4): 146–9. PMID 15162797.
Further reading
Further reading
- Graff, JW; et al. (2005). “The VHL Handbook: What You Need to Know about VHL”. VHL Family Alliance. 12 (1): 1–56.
- Lonser RR (2003). “Von Hippel-Lindau Disease”. Lancet. 361 (9374): 2059–2067. PMID 12814730.
- Neumann HP, Wiestler OD (1991). “Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus”. Lancet. 337 (8749): 1052–4. PMID 1673491.
- Kamura T, Conaway JW, Conaway RC (2002). “Roles of SCF and VHL ubiquitin ligases in regulation of cell growth”. Prog. Mol. Subcell. Biol. 29: 1–15. PMID 11908068.
- Kaelin WG (2002). “Molecular basis of the VHL hereditary cancer syndrome”. Nat. Rev. Cancer. 2 (9): 673–82. doi:10.1038/nrc885. PMID 12209156.
- Conaway RC, Conaway JW (2003). “The von Hippel-Lindau tumor suppressor complex and regulation of hypoxia-inducible transcription”. Adv. Cancer Res. 85: 1–12. PMID 12374282.
- Czyzyk-Krzeska MF, Meller J (2004). “von Hippel-Lindau tumor suppressor: not only HIF’s executioner”. Trends in molecular medicine. 10 (4): 146–9. PMID 15162797.
- Kaelin WG (2004). “The von Hippel-Lindau tumor suppressor gene and kidney cancer”. Clin. Cancer Res. 10 (18 Pt 2): 6290S–5S. doi:10.1158/1078-0432.CCR-sup-040025. PMID 15448019.
- Kralovics R, Skoda RC (2005). “Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders”. Blood Rev. 19 (1): 1–13. doi:10.1016/j.blre.2004.02.002. PMID 15572213.
- Schipani E (2006). “Hypoxia and HIF-1 alpha in chondrogenesis”. Semin. Cell Dev. Biol. 16 (4–5): 539–46. doi:10.1016/j.semcdb.2005.03.003. PMID 16144691.
- Russell RC, Ohh M (2007). “The role of VHL in the regulation of E-cadherin: a new connection in an old pathway”. Cell Cycle. 6 (1): 56–9. PMID 17245122.
- Kaelin WG (2007). “The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma”. Clin. Cancer Res. 13 (2 Pt 2): 680s–684s. doi:10.1158/1078-0432.CCR-06-1865. PMID 17255293.
External links
External links
- Von+Hippel-Lindau+Tumor+Suppressor+Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
- Esteban M, Harten S, Tran M, Maxwell P (2006). “Formation of primary cilia in the renal epithelium is regulated by the von hippel-lindau tumor suppressor protein”. J Am Soc Nephrol. 17 (7): 1801–6. PMID 16775032.
- Takahashi K, Iida K, Okimura Y, Takahashi Y, Naito J, Nishikawa S, Kadowaki S, Iguchi G, Kaji H, Chihara K (2006). “A novel mutation in the von Hippel-Lindau tumor suppressor gene identified in a Japanese family with pheochromocytoma and hepatic hemangioma”. Intern Med. 45 (5): 265–9. PMID 16595991.
- Hoebeeck J, Vandesompele J, Nilsson H, De Preter K, Van Roy N, De Smet E, Yigit N, De Paepe A, Laureys G, Påhlman S, Speleman F (2006). “The von Hippel-Lindau tumor suppressor gene expression level has prognostic value in neuroblastoma”. Int J Cancer. 119 (3): 624–9. PMID 16506218.