VHL suppressor gene

Von Hippel–Lindau tumor suppressor


The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, is encoded by the VHL gene. 


Mutations of the VHL gene are associated with Von Hippel–Lindau disease.


VHL encodes for 4 different isoforms.


Chromosome 3 


The Von Hippel–Lindau syndrome (VHL) is a dominantly inherited hereditary cancer syndrome.


Mutations leading to VHL loss of function result in a number of diseases including the VHL syndrome, an inherited disorder due to the germline VHL  alterations.


These  VHL alterations  lead to a predisposition to a somatic second hit, causing of a variety of tumors and fluid filled cysts, sporadic tumors, such as cerebellar hemangioblastoma, pheochromocytoma, clear cell renal cell carcinoma, familial erythrocytosis type two, that result in increased expression of HIF  target genes.

VHL, loss leads to stabilization of the transcription factors HIF – 1 alpha and HIF 2 alpha, which induce anaerobic metabolism, and tumor growth, respectively.

HIF-27 alpha is a key driver of renal cell carcinoma tumorogenesis.

Oxygen sensing pathways allow adjustments that alter function and survival of cells under a variety of conditions, and this  hypoxic response is sensitive.


The hypoxic response respond  to small changes with transcriptional and post transcriptional responses. 

The process of the degradation of the hypoxia-inducible factors (HIFs) that mainly regulate oxygen and iron dependent activity of enzymes require DHL tumor suppressor.


The Von Hippel–Lindau syndrome (VHL) predisposes to a variety of malignant and benign tumors of the eye, brain, spinal cord, kidney, pancreas, and adrenal glands. 


Increased HIF levels caused by VHL loss of function causes many diseases with different features.


The VHL syndrome, generally caused by hereditary allele inactivation plus a tissue somatic mutation, is characterized by the occurrence of malignancies and increased expression of oncogenic genes, including VEGF, that allow tumor development and progression.


The VHL syndrome is inherited by  one mutation in the VHL protein that causes the protein’s normal function to be lost or altered. 


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


Under normal oxygen levels, HIF1α binds pVHL and is polyubiquitinated by pVHL: 


leading to its degradation via the proteasome. 


During hypoxia, the proline residues are not hydroxylated and pVHL cannot bind. 


HIF1α causes the transcription of genes that contain the hypoxia response element. 


In VHL disease, genetic mutations cause alterations to the pVHL protein, usually to the HIF1α binding site.


The protein functions as a tumor suppressor. 


The main action of the VHL protein is  ubiquitin ligase activity resulting  in protein degradation.


The most studied target  of VHL is hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors.


HIF is necessary for tumor growth.


Most cancers demand high metabolic activity and are only supplied by structurally or functionally inadequate vasculature. 


Activation of HIF enhances angiogenesis, which in turn allows for increased glucose uptake. 


HIF is mostly active in hypoxic conditions.


VHL-defective renal carcinoma cells show activation of HIF even in oxygenated environments.


VHL and HIF interact closely.


In normal cells in hypoxic conditions, HIF1A is activated with little activation of HIF2A. 


In  alignancy  the balance of HIF1A and HIF2A is tipped towards HIF2A. 


HIF1A serves as a pro-apoptotic factor.


HIF2A interacts with cyclin D1, leading  to increased survival due to lower rates of apoptosis and increased proliferation due to the activation of cyclin D1.


HIF1A binds upstream of majorly good prognosis genes, while HIF2A binds upstream to majorly poor prognosis genes. 


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 ubiquitylation of HIF1A, ensuring that this protein will be degraded by the proteasome. 


In hypoxia, HIF1A subunits accumulate and bind to HIFB. 


This heterodimer of HIF 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 formation of these dimers, and behave like they are hypoxic even in oxygenated environments.


HIF is linked to mTOR, a central controller of cellular growth.


HIF activation can inactivate mTOR.


Loss of VHL function leads to constitutive activation of HIF and its downstream effects. 


Type 2 VHL missense mutations and is linked to a high risk of pheochromocytoma. 


Type 2 can be subdivided based on risks of renal cell carcinoma. 


In types 1, 2A and 2B the mutant pVHL is defective in HIF regulation.


In type 2C mutant there is a  defect in protein kinase C regulation.


Missense mutations of pVHL lead to a ‘gain of function’ protein.


Renal cells are more sensitive to the effects of growth factors created downstream of HIF activation than other cells. 


Many cells in the kidney normally operate under hypoxic conditions. 


The VHL protein can associate with tubulin, and is capable of stabilizing and elongating microtubules. 


The VHL protein can help stabilize of the spindle during mitosis. 


Deletion of VHL protein causes an increase of misorientated and rotating spindles during mitosis, and increases the concentration of MAD2, an important protein of the spindle checkpoint. 


As a result of VHL-loss there is a weakened checkpoint and chromosome missegregation and aneuploidy.


The loss of VHL protein activity results in an increased amount of HIF1a:  increased levels of angiogenic factors, including VEGF and PDGF. 


Increased angiogenic factors lead to unregulated blood vessel growth, a prerequisite of a tumor. 


The VHL gene has been implicated in maintaining the differentiated phenotype in renal cells.


pVHL is important, in addition, for extracellular matrix formation, and inhibition of matrix metalloproteinases, important in the metastasis of VHL-deficient cells. 


Targets for VHL-related cancers include targets of the HIF pathway, such as VEGF. 


Inhibitors of VEGF receptor includes: sorafenib, sunitinib, pazopanib, and axitinib.


mTOR inhibitor rapamycin analogs everolimus and temsirolimus or VEGF monoclonal antibody bevacizumab may also be an option.


Iron, 2-oxoglutarate and oxygen are necessary for the inactivation of HIF?


In cells with a high activation of HIF reversal can occur by supplying the cells with ascorbate.





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