biology

Von Hippel–Lindau tumor suppressor

Von Hippel–Lindau tumor suppressor is a biology topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Von Hippel–Lindau tumor suppressor rather than just read about it. In short: The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina.

Key takeaways

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Reference excerpt

The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.

Function The protein encoded by the VHL gene is the substrate recognition component of a protein complex that includes elongin B, elongin C, and cullin-2, and possesses E3 ubiquitin ligase activity. This complex is involved in the ubiquitination and subsequent degradation of hypoxia-inducible factors (HIFs), which are transcription factors that play a central role regulating gene expression in response to changing oxygen levels. 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 resultant protein is produced in two forms, an 18 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 hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors. HIFs are necessary for tumor growth because most cancers demand high metabolic activity and are only supplied by structurally or functionally inadequate vasculature. Activation of HIFs allow for enhanced angiogenesis, which in turn allow for increased glucose uptake. While HIFs are 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 HIFs 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. Recent genome-wide analysis (GWAS) of HIF binding in kidney cancer showed that HIF1A binds upstream of majorly good prognosis genes, while HIF2A binds upstream to majorly poor prognosis genes. This indicates that the HIF transcription factor distribution in kidney cancer is of major importance in determining the outcome of the patients. 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 product 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 erythropoietin, 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 mTOR, a central controller of growth decisions. It has recently been shown that HIF activation can inactivate mTOR. 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. These genotype–phenotype correlations suggest that missense mutations of pVHL lead to a '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 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 or downregulation of VHL causes a drastic increase of misorientated and rotating spindles during mitosis. Through a not-yet-known mechanism, VHL also increases the concentration of MAD2, an important protein of the spindle checkpoint. Also, VHL colocalizes with the microtubule. Thus VHL loss leads to a weakened checkpoint and subsequently chromosome missegregation and aneuploidy.

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Illustrations

Worked examples

Example 1 — a first encounter with Von Hippel–Lindau tumor suppressor

Start with the simplest possible case. Write down what Von Hippel–Lindau tumor suppressor claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Von Hippel–Lindau tumor suppressor before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Von Hippel–Lindau tumor suppressor ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Von Hippel–Lindau tumor suppressor

In research: Von Hippel–Lindau tumor suppressor appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Von Hippel–Lindau tumor suppressor in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Von Hippel–Lindau tumor suppressor is common in secondary-school and first-year university syllabi. It links to neighbouring topics EC 6.3, Genes on human chromosome 3, Tumor suppressor genes, so understanding it makes those chapters shorter.
In everyday life: Look for Von Hippel–Lindau tumor suppressor outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Von Hippel–Lindau tumor suppressor in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Von Hippel–Lindau tumor suppressor means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
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Frequently asked questions

What is Von Hippel–Lindau tumor suppressor in simple terms?

Why does Von Hippel–Lindau tumor suppressor matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Von Hippel–Lindau tumor suppressor?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Von Hippel–Lindau tumor suppressor.