Von Hippel-Lindau tumor suppressor

Von Hippel-Lindau tumor suppressor

The Von Hippel-Lindau tumor suppressor protein is encoded by the VHL gene and when inactivated is associated with Von Hippel-Lindau disease.

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summary_text = Von Hippel-Lindau syndrome (VHL) is a dominantly inherited hereditary 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. Individuals with VHL syndrome inherit one mutation in the VHL protein that causes the protein's normal function to be lost or altered. Over time, sporadic mutation in the second copy of the VHL protein can lead to carcinomas.

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 complex is involved in the ubiquitination and degradation of a 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. [cite web | title = Entrez Gene: VHL von Hippel-Lindau tumor suppressor| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7428| accessdate = ]

The disease is caused by mutations of the "VHL" gene on the short arm of the third chromosome (3p26-p25).


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. [cite journal |author=Czyzyk-Krzeska MF, Meller J |title=von Hippel-Lindau tumor suppressor: not only HIF's executioner |journal=Trends in molecular medicine |volume=10 |issue=4 |pages=146–9 |year=2004 |pmid=15162797 |doi=]

HIF is necessary for tumor growth because most cancers demand high metabolic activity and are only supplied by structurally or functionally inadequate vasculature. Activation of HIF allows for enhanced angiogenesis, which in turn allows for increased glucose intake. While HIF is mostly active in hypoxic conditions, VHL-defective renal carcinoma cells show constitutive activation of HIF even in oxygenated environments.

It is clear that VHL and HIF interact closely. Firstly, all renal cell carcinoma mutations in VHL that have been tested affect the protein's ability to modify HIF. Additionally, HIF activation can be detected in the earliest events in tumorigenesis in patients with VHL syndrome. In normal cells in hypoxic conditions, HIF1A is activated with little activation of HIF2A. However, in tumors the balance of HIF1A and HIF2A is tipped towards HIF2A. While HIF1A serves as a pro-apoptotic factor, HIF2A interacts with Cyclin D1. This leads to increased survival due to lower rates of apoptosis and increased proliferation due to the activation of Cyclin D1 [Maxwell, 2005] .

In the normal cell with active VHL protein, HIF alpha is regulated by hydroxylation in the presence of oxygen. When iron, 2-oxoglutarate and oxygen are present, HIF is inactivated by HIF hydroxylases. Hydroxylation of HIF creates a binding site for pVHL (the protein transcript of the VHL gene) [cite journal |author=Kaelin, WG |title=The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma |journal=Clinical Cancer Research |volume=13 |issue=2 Suppl |pages=680s-684s |year=2007 |doi=10.1158/1078-0432.CCR-06-1865] . pVHL directs the polyubiquitylation of HIF1A, ensuring that this protein will be degraded by proteases. In hypoxic conditions, HIF1A subunits accumulate and bind to HIFB. This heterodimer of HIF is a transcription factor that activates genes that encode for proteins such as vascular endothelial growth factor (VEGF) and erthyropoietin, proteins that a both involved in angiogenesis. Cells with abnormal pVHL are unable to disrupt the formation of these dimers, and therefore behave like they are hypoxic even in oxygenated environments.

HIF has also been linked to mTOR, a central controller of growth decisions. It has recently been shown that HIF activation can inactivate mTOR [cite journal |author=Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, et al. |title=Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. |journal=Genes & Development |volume=18 |pages=2893–904 |year=2004 |doi=10.1101/gad.1256804] .

Interestingly, HIF can help explain the organ specific nature of VHL syndrome. It has been theorized that constitutively activating HIF in any cell could lead to cancer, but that there are redundant regulators of HIF in organs not affected by VHL syndrome. This theory has been disproved multiple times since in all cell types loss of VHL function leads to constitutive activation of HIF and its downstream effects. Another theory holds that although in all cells loss of VHL leads to activation of HIF, in "most" cells this leads to no advantage in proliferation or survival. Additionally, the nature of the mutation in the VHL protein leads to phenotypic manifestations in the pattern of cancer that develops. Nonsense or deletion mutations of VHL protein have been linked to type 1 VHL with a low risk of pheochromocytoma (adrenal gland tumors). Type 2 VHL has been linked to missense mutations and is linked to a high risk of pheochromocytoma. Type 2 has also been further subdivided based on risks of renal cell carcinoma. In types 1, 2A and 2B the mutant pVHL is defective in HIF regulation, while type 2C mutant are defective in [protein kinase C] regulation [Kaelin, 2007] . These genotype-phenotype correlations suggest that missense mutations of pVHL lead to a 'gain of function' protein [cite journal |author=Kaelin, WG |title= Molecular Basis of the VHL Hereditary Cancer Syndrome |journal=Nature Reviews Cancer |volume= 2 |pages=673–682 |year= 2002 |doi= 10.1038/nrc885] .

The involvement in VHL in renal cell cancer can be rationalized via multiple characteristics of renal cells. First, they are more sensitive to the affects of growth factors created downstream of HIF activation than other cells. Secondly, the link to Cyclin D1 (as mentioned above) is only seen in renal cells. Finally, many cells in the kidney normally operate under hypoxic conditions. This may give them a proliferative advantage over other cells while in hypoxic environments [Kaelin, 2007] .


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. Additionally, VHL has been implicated in maintaining the differentiated phenotype in renal cells [Maxwell, 2005] . Furthermore, "in vitro" experiments with VHL -/- cells have shown that the addition of pVHL can induce a mesenchymal to epithelial transition. This evidence suggests that VHL has a central role in maintaining a differentiated phenotype in the cell [Kaelin, 2007] .

Additionally, pVHL is important for extracellular matrix formation [Kaelin, 2002] . This protein may also be important in inhibition of matrix metalloproteinases. These ideas are extremely important in the metastasis of VHL-deficient cells.


Suggested targets for VHL-related cancers include targets of the HIF pathway, such as VEGF. Two inhibitors of VEGF sorafenib and sunitinib have recently been approved by the FDA [Kaelin, 2007] . The mTOR inhibitor rapamycin may also be an option [cite journal |author=Kaelin, WG |title=The von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer |journal= Clinical Cancer Research |volume 10 |pages=6290s-6295s |year=2004 |doi=10.1158/1078-0432.CCR-sup-040025 |volume=10 ] . Bevacizumab, a monoclonal antibody targeting VEGF, is one medication currently undergoing clinical trials

Since iron, 2-oxoglutarate and oxygen are necessary for the inactivation of HIF, it has been theorized that a lack of these cofactors could reduce the ability of hydroxlases in inactivating HIF. A recent study has shown that in cells with a high activation of HIF even in oxygenated environments was reversed by supplying the cells with ascorbate [cite journal |author=Knowles HJ, Raval RR, Harris AL, Ratcliffe, PJ. |title=Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. |journal=Cancer research |volume=63 |pages=1764–8 |year=2003 ] . Thus, Vitamin C may be a potential treatment for HIF induced tumors.

ee also

*Von Hippel Lindau Binding protein 1


Further reading

*cite journal | author=Graff, JW et al |title=The VHL Handbook: What You Need to Know about VHL. |journal=VHL Family Alliance |volume=12 |issue= 1 |pages= 1–56 |year= 2005 |pmid=|doi=
*cite journal | author=Lonser RR |title=Von Hippel-Lindau Disease. |journal=Lancet |volume=361 |issue= 9374 |pages= 2059–2067 |year= 2003 |pmid= 12814730 |doi= PBB_Further_reading
citations =
*cite journal | author=Neumann HP, Wiestler OD |title=Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. |journal=Lancet |volume=337 |issue= 8749 |pages= 1052–4 |year= 1991 |pmid= 1673491 |doi=
*cite journal | author=Kamura T, Conaway JW, Conaway RC |title=Roles of SCF and VHL ubiquitin ligases in regulation of cell growth. |journal=Prog. Mol. Subcell. Biol. |volume=29 |issue= |pages= 1–15 |year= 2002 |pmid= 11908068 |doi=
*cite journal | author=Kaelin WG |title=Molecular basis of the VHL hereditary cancer syndrome. |journal=Nat. Rev. Cancer |volume=2 |issue= 9 |pages= 673–82 |year= 2002 |pmid= 12209156 |doi= 10.1038/nrc885
*cite journal | author=Conaway RC, Conaway JW |title=The von Hippel-Lindau tumor suppressor complex and regulation of hypoxia-inducible transcription. |journal=Adv. Cancer Res. |volume=85 |issue= |pages= 1–12 |year= 2003 |pmid= 12374282 |doi=
*cite journal | author=Czyzyk-Krzeska MF, Meller J |title=von Hippel-Lindau tumor suppressor: not only HIF's executioner. |journal=Trends in molecular medicine |volume=10 |issue= 4 |pages= 146–9 |year= 2004 |pmid= 15162797 |doi=
*cite journal | author=Kaelin WG |title=The von Hippel-Lindau tumor suppressor gene and kidney cancer. |journal=Clin. Cancer Res. |volume=10 |issue= 18 Pt 2 |pages= 6290S–5S |year= 2004 |pmid= 15448019 |doi= 10.1158/1078-0432.CCR-sup-040025
*cite journal | author=Kralovics R, Skoda RC |title=Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders. |journal=Blood Rev. |volume=19 |issue= 1 |pages= 1–13 |year= 2005 |pmid= 15572213 |doi= 10.1016/j.blre.2004.02.002
*cite journal | author=Schipani E |title=Hypoxia and HIF-1 alpha in chondrogenesis. |journal=Semin. Cell Dev. Biol. |volume=16 |issue= 4-5 |pages= 539–46 |year= 2006 |pmid= 16144691 |doi= 10.1016/j.semcdb.2005.03.003
*cite journal | author=Russell RC, Ohh M |title=The role of VHL in the regulation of E-cadherin: a new connection in an old pathway. |journal=Cell Cycle |volume=6 |issue= 1 |pages= 56–9 |year= 2007 |pmid= 17245122 |doi=
*cite journal | author=Kaelin WG |title=The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. |journal=Clin. Cancer Res. |volume=13 |issue= 2 Pt 2 |pages= 680s-684s |year= 2007 |pmid= 17255293 |doi= 10.1158/1078-0432.CCR-06-1865

External links


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