"VHL" redirects here. For the Vysshaya Khokkeynaya Liga (VHL, Russian: Высшая хоккейная лига (ВХЛ)) hockey league, see Higher Hockey League.
| Von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase |
PDB rendering based on 1lm8. |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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1LM8, 1LQB, 1VCB, 3ZRC, 3ZRF, 3ZTC, 3ZTD, 3ZUN, 4AJY, 4AWJ, 4B95, 4B9K, 4BKS, 4BKT
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| Identifiers |
| Symbols |
VHL ; HRCA1; RCA1; VHL1; pVHL |
| External IDs |
OMIM: 608537 MGI: 103223 HomoloGene: 465 GeneCards: VHL Gene |
| Gene ontology |
| Molecular function |
• ubiquitin-protein transferase activity
• protein binding
• transcription factor binding
• enzyme binding
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| Cellular component |
• nucleus
• nucleoplasm
• nucleolus
• mitochondrion
• endoplasmic reticulum
• cytosol
• membrane
• intermediate filament cytoskeleton
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| Biological process |
• negative regulation of transcription from RNA polymerase II promoter
• cell morphogenesis
• regulation of transcription, DNA-templated
• proteolysis
• response to stress
• negative regulation of cell proliferation
• protein ubiquitination
• negative regulation of apoptotic process
• positive regulation of cell differentiation
• positive regulation of transcription, DNA-templated
• protein stabilization
• regulation of transcription from RNA polymerase II promoter in response to hypoxia
• negative regulation of transcription from RNA polymerase II promoter in response to hypoxia
• cellular response to hypoxia
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
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| Entrez |
7428 |
22346 |
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| Ensembl |
ENSG00000134086 |
ENSMUSG00000033933 |
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| UniProt |
P40337 |
P40338 |
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| RefSeq (mRNA) |
NM_000551 |
NM_009507 |
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| RefSeq (protein) |
NP_000542 |
NP_033533 |
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| Location (UCSC) |
Chr 3:
10.18 – 10.19 Mb |
Chr 6:
113.62 – 113.63 Mb |
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| PubMed search |
[1] |
[2] |
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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.
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, 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 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.[1]
The disease is caused by mutations of the VHL gene on the short arm of the third chromosome (3p26–p25).
Contents
- 1 Function
- 2 Pathology
- 3 Treatment
- 4 Interactions
- 5 See also
- 6 References
- 7 Further reading
- 8 External links
Function
The regulation of HIF1α by pVHL. Under normal oxygen levels, HIF1α binds pVHL through 2 hydroxylated proline residues and is polyubiquitinated by pVHL. This leads 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 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.[2]
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.[3]
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).[4] 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 mTOR, a central controller of growth decisions. It has recently been shown that HIF activation can inactivate mTOR.[5]
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.[6] These genotype–phenotype correlations suggest that missense mutations of pVHL lead to a 'gain of function' protein.[7]
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.[6]
In addition to its interaction with HIF the VHL protein can also associate with tubulin.[8] 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 MAD2, an important protein of the spindle checkpoint. Thus VHL-loss leads to a weakened checkpoint and subsequently chromosome missegregation and 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 angiogenic factors, including VEGF and PDGF. In turn, this leads to unregulated blood vessel growth, one of the prerequisites of a tumor. Additionally, VHL has been implicated in maintaining the differentiated phenotype in renal cells.[3] 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.[6]
Additionally, pVHL is important for extracellular matrix formation.[9] 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.[10]
Treatment
Suggested targets for VHL-related cancers include targets of the HIF pathway, such as VEGF. Inhibitors of VEGF receptor sorafenib, sunitinib, pazopanib, and recently axitinib have been approved by the FDA.[6] The mTOR inhibitor rapamycin[11] analogs everolimus and temsirolimus or VEGF monoclonal antibody 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.[12] Thus, Vitamin C may be a potential treatment for HIF induced tumors.
Interactions
Von Hippel–Lindau tumor suppressor has been shown to interact with CCDC82,[13] USP33,[14] PHF17,[15] SAP130,[16] HIF1AN,[17] Nerve Growth factor IB,[18] Filamin,[15][19] TCEB1,[14][18][19][20][21][22][23] PSMC3,[24] CUL2,[16][20][21][23][25] HIF1A[17][18][22][24][26][27][28][29][30][31] and TCEB2.[16][20][21][22][23]
See also
- Von Hippel Lindau Binding protein 1
References
- ^ "Entrez Gene: VHL von Hippel–Lindau tumor suppressor".
- ^ Czyzyk-Krzeska MF, Meller J (2004). "von Hippel–Lindau tumor suppressor: not only HIF's executioner". Trends in molecular medicine 10 (4): 146–9. doi:10.1016/j.molmed.2004.02.004. PMID 15162797.
- ^ a b Maxwell, 2005
- ^ Kaelin, WG (2007). "The von Hippel–Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma". Clinical Cancer Research 13 (2 Suppl): 680s–684s. doi:10.1158/1078-0432.CCR-06-1865. PMID 17255293.
- ^ Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, et al. (2004). "Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.". Genes & Development 18 (23): 2893–904. doi:10.1101/gad.1256804. PMC 534650. PMID 15545625.
- ^ a b c d Kaelin, 2007
- ^ Kaelin, WG (2002). "Molecular Basis of the VHL Hereditary Cancer Syndrome". Nature Reviews Cancer 2 (9): 673–682. doi:10.1038/nrc885. PMID 12209156.
- ^ Lolkema MP, Mehra N, Jorna AS, van Beest M, Giles RH, Voest EE (December 2004). "The von Hippel–Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery". Exp. Cell Res. 301 (2): 139–46. doi:10.1016/j.yexcr.2004.07.016. PMID 15530850.
- ^ Kaelin, 2002
- ^ Formenti F, Beer PA, Croft QPP, Dorrington KL, Gale DP, Lappin TRJ, Lucas GS, Maher ER, Maxwell PH, McMullin MF, O'Connor DF, Percy MJ, Pugh CW, Ratcliffe PJ, Smith TG, Talbot NP and Robbins PA (March 2011). "Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2α gain-of-function mutation". The FASEB Journal (United States) 25 (6): 2001–11. doi:10.1096/fj.10-177378. PMC 3159892. PMID 21389259.
- ^ Kaelin, WG (2004). "The von Hippel–Lindau Tumor Suppressor Gene and Kidney Cancer". Clinical Cancer Research 10 (18 Pt 2): 6290s–6295s. doi:10.1158/1078-0432.CCR-sup-040025. PMID 15448019.
- ^ Knowles HJ, Raval RR, Harris AL, Ratcliffe, PJ. (2003). "Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells". Cancer Research 63 (8): 1764–8. PMID 12702559.
- ^ "CCDC82 Pathways/Interactions". Gene Cards. Weizmann Institute of Science.
- ^ a b Li, Zaibo; Na Xi; Wang Dakun; Schoen Susan R; Messing Edward M; Wu Guan (February 2002). "Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel–Lindau tumor suppressor protein". J. Biol. Chem. (United States) 277 (7): 4656–62. doi:10.1074/jbc.M108269200. ISSN 0021-9258. PMID 11739384.
- ^ a b Zhou, Mina I; Wang Hongmei; Ross Jonathan J; Kuzmin Igor; Xu Chengen; Cohen Herbert T (October 2002). "The von Hippel–Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1". J. Biol. Chem. (United States) 277 (42): 39887–98. doi:10.1074/jbc.M205040200. ISSN 0021-9258. PMID 12169691.
- ^ a b c Menon, Suchithra; Tsuge Tomohiko; Dohmae Naoshi; Takio Koji; Wei Ning (2008). "Association of SAP130/SF3b-3 with Cullin-RING ubiquitin ligase complexes and its regulation by the COP9 signalosome". BMC Biochem. (England) 9: 1. doi:10.1186/1471-2091-9-1. PMC 2265268. PMID 18173839.
- ^ a b Mahon, P C; Hirota K; Semenza G L (October 2001). "FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity". Genes Dev. (United States) 15 (20): 2675–86. doi:10.1101/gad.924501. ISSN 0890-9369. PMC 312814. PMID 11641274.
- ^ a b c Kim, Bu Yeon; Kim Hyungsoo; Cho Eun Jung; Youn Hong Duk (February 2008). "Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation". Exp. Mol. Med. (Korea (South)) 40 (1): 71–83. doi:10.3858/emm.2008.40.1.71. ISSN 1226-3613. PMC 2679322. PMID 18305400.
- ^ a b Tsuchiya, H; Iseda T; Hino O (July 1996). "Identification of a novel protein (VBP-1) binding to the von Hippel–Lindau (VHL) tumor suppressor gene product". Cancer Res. (UNITED STATES) 56 (13): 2881–5. ISSN 0008-5472. PMID 8674032.
- ^ a b c Ewing, Rob M; Chu Peter, Elisma Fred, Li Hongyan, Taylor Paul, Climie Shane, McBroom-Cerajewski Linda, Robinson Mark D, O'Connor Liam, Li Michael, Taylor Rod, Dharsee Moyez, Ho Yuen, Heilbut Adrian, Moore Lynda, Zhang Shudong, Ornatsky Olga, Bukhman Yury V, Ethier Martin, Sheng Yinglun, Vasilescu Julian, Abu-Farha Mohamed, Lambert Jean-Philippe, Duewel Henry S, Stewart Ian I, Kuehl Bonnie, Hogue Kelly, Colwill Karen, Gladwish Katharine, Muskat Brenda, Kinach Robert, Adams Sally-Lin, Moran Michael F, Morin Gregg B, Topaloglou Thodoros, Figeys Daniel (2007). "Large-scale mapping of human protein–protein interactions by mass spectrometry". Mol. Syst. Biol. (England) 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
- ^ a b c Ohh, M; Takagi Y; Aso T; Stebbins C E; Pavletich N P; Zbar B; Conaway R C; Conaway J W; Kaelin W G (Dec 1999). "Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel–Lindau protein". J. Clin. Invest. (UNITED STATES) 104 (11): 1583–91. doi:10.1172/JCI8161. ISSN 0021-9738. PMC 481054. PMID 10587522.
- ^ a b c Min, Jung-Hyun; Yang Haifeng; Ivan Mircea; Gertler Frank; Kaelin William G; Pavletich Nikola P (June 2002). "Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling". Science (United States) 296 (5574): 1886–9. doi:10.1126/science.1073440. PMID 12004076.
- ^ a b c Hacker, Kathryn E; Lee Caroline Martz; Rathmell W Kimryn (2008). "VHL type 2B mutations retain VBC complex form and function". In Zhang, Baohong. PLoS ONE (United States) 3 (11): e3801. doi:10.1371/journal.pone.0003801. PMC 2583047. PMID 19030229.
- ^ a b Corn, Paul G; McDonald E Robert, Herman James G, El-Deiry Wafik S (November 2003). "Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel–Lindau protein". Nat. Genet. (United States) 35 (3): 229–37. doi:10.1038/ng1254. ISSN 1061-4036. PMID 14556007.
- ^ Kamura, T; Burian D; Yan Q; Schmidt S L; Lane W S; Querido E; Branton P E; Shilatifard A; Conaway R C; Conaway J W (August 2001). "Muf1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase". J. Biol. Chem. (United States) 276 (32): 29748–53. doi:10.1074/jbc.M103093200. ISSN 0021-9258. PMID 11384984.
- ^ Li, Zaibo; Wang Dakun; Na Xi; Schoen Susan R; Messing Edward M; Wu Guan (April 2003). "The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity". EMBO J. (England) 22 (8): 1857–67. doi:10.1093/emboj/cdg173. ISSN 0261-4189. PMC 154465. PMID 12682018.
- ^ Tanimoto, K; Makino Y; Pereira T; Poellinger L (August 2000). "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel–Lindau tumor suppressor protein". EMBO J. (ENGLAND) 19 (16): 4298–309. doi:10.1093/emboj/19.16.4298. ISSN 0261-4189. PMC 302039. PMID 10944113.
- ^ Yu, F; White S B; Zhao Q; Lee F S (August 2001). "HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (17): 9630–5. doi:10.1073/pnas.181341498. ISSN 0027-8424. PMC 55503. PMID 11504942.
- ^ Jung, Joo Eun; Kim Hong Sook, Lee Chang Seok, Shin Yong Jae, Kim Yong Nyun, Kang Gyeong Hoon, Kim Tae You, Juhnn Yong Sung, Kim Sung Joon, Park Jong Wan, Ye Sang Kyu, Chung Myung Hee (October 2008). "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Exp. Mol. Med. (Korea (South)) 40 (5): 479–85. doi:10.3858/emm.2008.40.5.479. ISSN 1226-3613. PMC 2679355. PMID 18985005.
- ^ André, Helder; Pereira Teresa S (October 2008). "Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha". J. Biol. Chem. (United States) 283 (43): 29375–84. doi:10.1074/jbc.M805919200. ISSN 0021-9258. PMC 2662024. PMID 18694926.
- ^ Park, Young-Kwon; Ahn Dae-Ro; Oh Myoungsuk; Lee Taekyoung; Yang Eun Gyeong; Son Miwon; Park Hyunsung (July 2008). "Nitric oxide donor, (+/-)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1alpha by inhibiting von Hippel–Lindau recruitment and asparagine hydroxylation". Mol. Pharmacol. (United States) 74 (1): 236–45. doi:10.1124/mol.108.045278. PMID 18426857.
Further reading
- Esteban M, Harten S, Tran M, Maxwell P (2006). "Formation of primary cilia in the renal epithelium is regulated by the von hippel–lindau tumor suppressor protein". J Am Soc Nephrol 17 (7): 1801–6. doi:10.1681/ASN.2006020181. PMID 16775032.
- 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". Intern Med 45 (5): 265–9. doi:10.2169/internalmedicine.45.1547. PMID 16595991.
- 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 (2006). "The von Hippel–Lindau tumor suppressor gene expression level has prognostic value in neuroblastoma". Int J Cancer 119 (3): 624–9. doi:10.1002/ijc.21888. PMID 16506218.
- Graff, JW et al. (2005). "The VHL Handbook: What You Need to Know about VHL". VHL Family Alliance 12 (1): 1–56.
- Lonser RR; Glenn, GM; Walther, M; Chew, EY; Libutti, SK; Linehan, WM; Oldfield, EH (2003). "Von Hippel–Lindau Disease". Lancet 361 (9374): 2059–2067. doi:10.1016/S0140-6736(03)13643-4. PMID 12814730.
- Neumann HP, Wiestler OD (1991). "Clustering of features of von Hippel–Lindau syndrome: evidence for a complex genetic locus". Lancet 337 (8749): 1052–4. doi:10.1016/0140-6736(91)91705-Y. PMID 1673491.
- Kamura T, Conaway JW, Conaway RC (2002). "Roles of SCF and VHL ubiquitin ligases in regulation of cell growth". Prog. Mol. Subcell. Biol. 29: 1–15. doi:10.1007/978-3-642-56373-7_1. PMID 11908068.
- Kaelin WG (2002). "Molecular basis of the VHL hereditary cancer syndrome". Nat. Rev. Cancer 2 (9): 673–82. doi:10.1038/nrc885. PMID 12209156.
- Conaway RC, Conaway JW (2003). "The von Hippel–Lindau tumor suppressor complex and regulation of hypoxia-inducible transcription". Adv. Cancer Res. 85: 1–12. doi:10.1016/S0065-230X(02)85001-1. PMID 12374282.
- Czyzyk-Krzeska MF, Meller J (2004). "von Hippel–Lindau tumor suppressor: not only HIF's executioner". Trends in molecular medicine 10 (4): 146–9. doi:10.1016/j.molmed.2004.02.004. PMID 15162797.
- Kaelin WG (2004). "The von Hippel–Lindau tumor suppressor gene and kidney cancer". Clin. Cancer Res. 10 (18 Pt 2): 6290S–5S. doi:10.1158/1078-0432.CCR-sup-040025. PMID 15448019.
- Kralovics R, Skoda RC (2005). "Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders". Blood Rev. 19 (1): 1–13. doi:10.1016/j.blre.2004.02.002. PMID 15572213.
- Schipani E (2006). "Hypoxia and HIF-1 alpha in chondrogenesis". Semin. Cell Dev. Biol. 16 (4–5): 539–46. doi:10.1016/j.semcdb.2005.03.003. PMID 16144691.
- Russell RC, Ohh M (2007). "The role of VHL in the regulation of E-cadherin: a new connection in an old pathway". Cell Cycle 6 (1): 56–9. doi:10.4161/cc.6.1.3668. PMID 17245122.
- Kaelin WG (2007). "The von Hippel–Lindau tumor suppressor protein and clear cell renal carcinoma". Clin. Cancer Res. 13 (2 Pt 2): 680s–684s. doi:10.1158/1078-0432.CCR-06-1865. PMID 17255293.
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 US National Library of Medicine Medical Subject Headings (MeSH)
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PDB gallery
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1lm8: Structure of a HIF-1a-pVHL-ElonginB-ElonginC Complex
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1lqb: Crystal structure of a hydroxylated HIF-1 alpha peptide bound to the pVHL/elongin-C/elongin-B complex
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1vcb: THE VHL-ELONGINC-ELONGINB STRUCTURE
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Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes
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| Ligand |
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| Receptor |
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Wnt signaling pathway
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Hedgehog signaling pathway
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TGF beta signaling pathway
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Receptor tyrosine kinase
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- ONCO: ErbB/c-ErbB
- c-Met
- c-Ret
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JAK-STAT signaling pathway
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| Intracellular signaling P+Ps |
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Wnt signaling pathway
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- ONCO: Beta-catenin
- TSP: APC
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TGF beta signaling pathway
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Akt/PKB signaling pathway
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Hippo signaling pathway
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TSP: Neurofibromin 2/Merlin
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MAPK/ERK pathway
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- TSP: Neurofibromin 1
- ONCO: c-Ras
- HRAS
- c-Raf
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Other/unknown
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| Nucleus |
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Cell cycle
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- TSP: p53
- pRb
- WT1
- p16/p14arf
- ONCO: CDK4
- Cyclin D
- Cyclin E
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DNA repair/Fanconi
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Ubiquitin ligase
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Transcription factor
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- TSP: KLF6
- ONCO: AP-1
- c-Myc
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| Mitochondria |
- Apoptosis inhibitor: SDHB
- SDHD
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| Other/ungrouped |
- c-Bcl-2 - Notch - Stathmin
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Enzymes: CO CS and CN ligases (EC 6.1-6.3)
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| 6.1: Carbon-Oxygen |
- Aminoacyl tRNA synthetase
- Tyrosine
- Tryptophan
- Threonine
- Leucine
- Isoleucine
- Lysine
- Alanine
- Valine
- Methionine
- Serine
- Aspartate
- D-alanine-poly(phosphoribitol) ligase
- Glycine
- Proline
- Cysteine
- Glutamate
- Glutamine
- Arginine
- Phenylalanine
- Histidine
- Asparagine
- Aspartate
- Glutamate
- Lysine
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| 6.2: Carbon-Sulfur |
- Succinyl coenzyme A synthetase - Acetyl Co-A synthetase - Long fatty acyl CoA synthetase
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| 6.3: Carbon-Nitrogen |
- Glutamine synthetase
- Ubiquitin ligase
- Cullin
- Von Hippel-Lindau tumor suppressor
- UBE3A
- Mdm2
- Anaphase-promoting complex
- UBR1
- Glutathione synthetase
- CTP synthase
- Adenylosuccinate synthase
- Argininosuccinate synthetase
- Holocarboxylase synthetase
- GMP synthase
- Asparagine synthetase
- Carbamoyl phosphate synthetase
- Gamma-glutamylcysteine synthetase
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- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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Ligases: carbon-carbon ligases (EC 6.4)
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| Biotin dependent carboxylase |
- Pyruvate carboxylase
- Acetyl-CoA carboxylase
- Propionyl-CoA carboxylase
- Methylcrotonyl-CoA carboxylase
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| Other |
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- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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Enzymes: Phosphoric ester and nitrogen-metal ligases (EC 6.5-6.6)
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| 6.5: Phosphoric Ester |
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| 6.6: Nitrogen-Metal |
- Magnesium chelatase
- Cobaltochelatase
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- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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Posttranslational modification
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Chaperones/
protein folding |
Heat shock proteins/
Chaperonins |
- Hsp10/GroES
- Hsp27
- Hsp47
- HSP60/GroEL
- Hsp40/DnaJ
- A1
- A2
- A3
- B1
- B2
- B11
- B4
- B6
- B9
- C1
- C3
- C5
- C6
- C7
- C10
- C11
- C13
- C14
- C19
- Hsp70
- 1A
- 1B
- 1L
- 2
- 4
- 4L
- 5
- 6
- 7
- 8
- 9
- 12A
- 14
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| Other |
- Alpha crystallin
- Clusterin
- Survival of motor neuron
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| Protein targeting |
- Signal peptide Mitochondrial targeting signal
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| Ubiquitin |
- E1 Ubiquitin-activating enzyme
- UBA1
- UBA2
- UBA3
- UBA5
- UBA6
- UBA7
- ATG7
- NAE1
- SAE1
- E2 Ubiquitin-conjugating enzyme
- A
- B
- C
- D1
- D2
- D3
- E1
- E2
- E3
- G1
- G2
- H
- I
- J1
- J2
- K
- L1
- L2
- L3
- L4
- L6
- M
- N
- O
- Q1
- Q2
- R1 (CDC34)
- R2
- S
- V1
- V2
- Z
- E3 Ubiquitin ligase
- VHL
- Cullin
- CBL
- MDM2
- FANCL
- UBR1
- Deubiquitinating enzyme: Ataxin 3
- USP6
- CYLD
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| Other |
- Ubiquitin-like modifiers
- SUMO protein
- ISG15
- URM1
- NEDD8
- FAT10
- ATG8
- ATG12
- FUB1
- MUB
- UFM1
- UBL5
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See also: posttranslational modification disorders
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
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