Von Hippel–Lindau tumor suppressor
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Location (UCSC) | Chr 3: 10.14 – 10.15 Mb | Chr 6: 113.6 – 113.61 Mb | |||||||
PubMed search | [3] | [4] |
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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. [5]
Function
The protein encoded by the VHL gene is the substrate recognition component of a protein complex that includes
The resultant protein is produced in two forms, an 18
The most researched of these targets is
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.[8] 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.[9]
In the normal cell with active VHL protein, HIF alpha is regulated by hydroxylation in the presence of oxygen. When iron,
HIF has also been linked to mTOR, a central controller of growth decisions. It has recently been shown that HIF activation can inactivate mTOR.[11]
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.[10] These genotype–phenotype correlations suggest that missense mutations of pVHL lead to a 'gain of function' protein.[12]
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.[10]
In addition to its interaction with HIF the VHL protein can also associate with
Pathology
The loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of
Additionally, pVHL is important for extracellular matrix formation.[12] This protein may also be important in inhibition of matrix metalloproteinases. These ideas are extremely important in the 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.[15]
Treatment
Suggested targets for VHL-related cancers include targets of the HIF pathway, such as VEGF. Inhibitors of VEGF receptor
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 hydroxylases 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.[17] Thus, Vitamin C may be a potential treatment for HIF induced tumors.
Interactions
Von Hippel–Lindau tumor suppressor has been shown to
See also
- Von Hippel–Lindau binding protein 1– Chaperone protein
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000134086 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033933 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 26279462.
- ^ "Entrez Gene: VHL von Hippel–Lindau tumor suppressor".
- PMID 15162797.
- ^ a b Maxwell, 2005
- PMID 26262842.
- ^ PMID 17255293.
- PMID 15545625.
- ^ S2CID 20186415.
- S2CID 37709417.
- S2CID 5287739.
- PMID 21389259.
- PMID 15448019.
- PMID 12702559.
- ^ PMID 18173839.
- ^ PMID 17353931.
- ^ PMID 10587522.
- ^ PMID 19030229.
- PMID 11384984.
- ^ PMID 12169691.
- ^ PMID 8674032.
- ^ PMID 11641274.
- ^ PMID 18305400.
- ^ S2CID 19641938.
- ^ S2CID 22798700.
- PMID 12682018.
- PMID 10944113.
- PMID 11504942.
- PMID 18985005.
- PMID 18694926.
- S2CID 31675735.
- ^ PMID 11739384.
Further reading
- Conaway RC, Conaway JW (2003). The von Hippel–Lindau tumor suppressor complex and regulation of hypoxia-inducible transcription. Vol. 85. pp. 1–12. )
- Czyzyk-Krzeska MF, Meller J (April 2004). "von Hippel–Lindau tumor suppressor: not only HIF's executioner". Trends in Molecular Medicine. 10 (4): 146–9. PMID 15162797.
- Esteban MA, Harten SK, Tran MG, Maxwell PH (July 2006). "Formation of primary cilia in the renal epithelium is regulated by the von Hippel–Lindau tumor suppressor protein". Journal of the American Society of Nephrology. 17 (7): 1801–6. PMID 16775032.
- 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 (August 2006). "The von Hippel–Lindau tumor suppressor gene expression level has prognostic value in neuroblastoma". International Journal of Cancer. 119 (3): 624–9. S2CID 632377.
- Kaelin WG (September 2004). "The von Hippel–Lindau tumor suppressor gene and kidney cancer". Clinical Cancer Research. 10 (18 Pt 2): 6290S–5S. PMID 15448019.
- Kaelin WG (January 2007). "The von Hippel–Lindau tumor suppressor protein and clear cell renal carcinoma". Clinical Cancer Research. 13 (2 Pt 2): 680s–684s. PMID 17255293.
- Kamura T, Conaway JW, Conaway RC (2002). "Roles of SCF and VHL Ubiquitin Ligases in Regulation of Cell Growth". Protein Degradation in Health and Disease. Progress in Molecular and Subcellular Biology. Vol. 29. pp. 1–15. PMID 11908068.
- Kralovics R, Skoda RC (January 2005). "Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders". Blood Reviews. 19 (1): 1–13. PMID 15572213.
- Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH (June 2003). "von Hippel–Lindau disease". Lancet. 361 (9374): 2059–67. S2CID 13783714.
- Neumann HP, Wiestler OD (May 1991). "Clustering of features of von Hippel–Lindau syndrome: evidence for a complex genetic locus". Lancet. 337 (8749): 1052–4. S2CID 24022884.
- Russell RC, Ohh M (January 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.
- Schipani E (2006). "Hypoxia and HIF-1 alpha in chondrogenesis". Seminars in Cell & Developmental Biology. 16 (4–5): 539–46. PMID 16144691.
- 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". Internal Medicine. 45 (5): 265–9. PMID 16595991.
- Graff JW (2005). "The VHL Handbook: What You Need to Know about VHL". VHL Family Alliance. 12 (1): 1–56.
External links
- VHL Alliance
- GeneReviews/NCBI/NIH/UW entry on Von Hippel–Lindau Syndrome or Angiomatosis Retinae, VHL Syndrome, von Hippel–Lindau Disease
- Von+Hippel–Lindau+Tumor+Suppressor+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)