Von Hippel–Lindau tumor suppressor

The Von Hippel–Lindau tumor suppressor also known as pVHL is a is_associated_with::protein that in humans is encoded by the VHL is_associated_with::gene. Mutations of the VHL gene are associated with is_associated_with::Von Hippel–Lindau disease.

Function
is_associated_with::Von Hippel–Lindau syndrome (VHL) is a dominantly inherited hereditary is_associated_with::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, in particular hemangioblastomas affecting the liver and kidneys, renal (and vaginal) clear cell adenocarcinomas.

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 is_associated_with::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.

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

The resultant protein is produced in two forms, an 18 is_associated_with::kDa and a 30 kDa protein that functions as a tumor suppressor. 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 is_associated_with::hypoxia inducible factor 1a (HIF1a), a is_associated_with::transcription factor that induces the expression of a number of is_associated_with::angiogenesis related factors.

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 is_associated_with::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 is_associated_with::Cyclin D1. This leads to increased survival due to lower rates of is_associated_with::apoptosis and increased proliferation due to the activation of Cyclin D1.

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). pVHL directs the polyubiquitylation of HIF1A, ensuring that this protein will be degraded by the proteasome. 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 are 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 is_associated_with::mTOR, a central controller of growth decisions. It has recently been shown that HIF activation can inactivate mTOR.

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 is_associated_with::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 is_associated_with::protein kinase C regulation. These genotype–phenotype correlations suggest that missense mutations of pVHL lead to a 'is_associated_with::gain of function' protein.

The involvement in VHL in renal cell cancer can be rationalized via multiple characteristics of renal cells. First, they are more sensitive to the effects 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.

In addition to its interaction with HIF the VHL protein can also associate with is_associated_with::tubulin. It is then capable to stabilize and thus elongate microtubules. This function plays a key role in the stabilisation of the spindle during mitosis. Deletion of VHL causes a drastic increase of misorientated and rotating spindles during mitosis. Through a not yet known mechanism VHL is also increases the concentration of is_associated_with::MAD2, an important protein of the spindle checkpoint. Thus VHL-loss leads to a weakened checkpoint and subsequently chromosome missegregation and is_associated_with::aneuploidy.

Pathology
It stands to reason that the loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of is_associated_with::angiogenic factors, including VEGF and is_associated_with::PDGF. In turn, this leads to unregulated is_associated_with::blood vessel growth, one of the prerequisites of a is_associated_with::tumor. Additionally, VHL has been implicated in maintaining the differentiated phenotype in renal cells. Furthermore, cell culture experiments with VHL -/- cells have shown that the addition of pVHL can induce a is_associated_with::mesenchymal to is_associated_with::epithelial transition. This evidence suggests that VHL has a central role in maintaining a differentiated phenotype in the cell.

Additionally, pVHL is important for is_associated_with::extracellular matrix formation. This protein may also be important in inhibition of matrix metalloproteinases. These ideas are extremely important in the is_associated_with::metastasis of VHL-deficient cells. In classical VHL disease a single wild-type allele in VHL appears to be sufficient to maintain normal cardiopulmonary function.

Treatment
Suggested targets for VHL-related cancers include targets of the HIF pathway, such as VEGF. Inhibitors of VEGF receptor is_associated_with::sorafenib, is_associated_with::sunitinib, is_associated_with::pazopanib, and recently is_associated_with::axitinib have been approved by the FDA. The mTOR inhibitor is_associated_with::rapamycin analogs is_associated_with::everolimus and is_associated_with::temsirolimus or VEGF monoclonal antibody is_associated_with::bevacizumab may also be an option.

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. Thus, is_associated_with::Vitamin C may be a potential treatment for HIF induced tumors.

Interactions
Von Hippel–Lindau tumor suppressor has been shown to interact with:


 * is_associated_with::CCDC82,
 * is_associated_with::CUL2,
 * is_associated_with::Filamin,
 * is_associated_with::HIF1AN,
 * is_associated_with::HIF1A,
 * is_associated_with::Nerve Growth factor IB,
 * is_associated_with::PHF17,
 * is_associated_with::PSMC3,
 * is_associated_with::SAP130,
 * is_associated_with::TCEB1,
 * is_associated_with::TCEB2,    and
 * is_associated_with::USP33.