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Genetic and Molecular Basis of Von Hippel-Lindau Disease: Comparison
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Von Hippel-Lindau disease (VHL disease or VHL syndrome) is a familial multisystem neoplastic disorder, stemming from germline disease-associated variants of the VHL tumor suppressor gene. VHL protein is involved in oxygen sensing and adaptive response to hypoxia through the EPO-VHL-HIF signaling axis. In recent years, numerous HIF-independent pathways of VHL have been identified, expanding the role of VHL throughout several cellular processes. In addition to VHL syndrome-associated tumors, VHL variations have also been associated with the development of eythrocytosis. Research indicated that there is a distinction between erythrocytosis-causing VHL variations and VHL variations causing VHL disease with tumor development. Therefore, elucidating the molecular background of the pathogenic effects of VHL variants could help determine the best approach to VHL disease management.  

  • VHL
  • VHL disease
  • Chuvash polycythemia
  • genetic variation
  • erythrocytosis
  • pheochromocytoma
  • renal cell carcinoma
  • retinal hemangioblastoma
  • hemangioblastoma

1. Introduction

Von Hippel-Lindau disease (VHL disease or VHL syndrome) is a familial multisystem syndrome stemming from germline disease-associated variants of the VHL tumor suppressor gene on chromosome 3 [1]. It is an autosomal dominant neoplastic disorder in which multiple benign and malignant tumors, as well as cysts, develop in the central nervous system (the brain, spinal cord, retina, and inner ear) and visceral organs (kidney, adrenal gland, pancreas, epididymis, and broad ligament) [2][3]. Despite its classification as a dominant disorder, the most common pattern in hereditary VHL disease is the inheritance of a germline genetic variant (herein, mutation) in one allele, followed by a second somatic change, leading to loss of the second allele [2][4][5]. In approximately 20% of cases, VHL syndrome is sporadic, caused by a de novo genetic change that arises during the formation of reproductive cells, or very early during the embryogenesis [4][6][7]. After the identification of the VHL gene in 1993, the phenotype of VHL pathogenic genetic variations was expanded to include VHL disease, dominantly inherited familial pheochromocytoma, and autosomal recessive familial polycythemia [8][9][10]. Chuvash polycythemia, a secondary congenital erythrocytosis, was the first congenital erythrocytosis linked to a VHL mutation [8]. Since then, several other VHL mutations associated with erythrocytosis have been identified [11].

2. VHL Canonical and Non-Canonical Functions

The von Hippel-Lindau tumor suppressor gene (VHL) is located on chromosome 3. Initially it was thought to be composed of three exons that encode the VHL protein [12][13]. Subsequent research revealed more complex transcription patterns, and an additional cryptic exon, resulting in several different functional VHL isoforms (Figure 1) [14][15]. Soon after its discovery, it was confirmed that the two most commonly isolated isoforms, VHL30 or VHL213 and VHL19 or VHL160, are both biologically active and are expressed in all tissues [16][17][18].
/media/item_content/202203/623bc422b0747genes-13-00362-g001.png
Figure 1. Schematic representation of VHL gene structure. (A). VHL gene structure and protein isoforms with corresponding VHL transcripts. (B). Putative VHL transcripts, containing exon E′, identified by cloning and sequencing [15].
VHL30 is the longest isoform, with a molecular mass of 30 kDa. It has 213 amino acids and consists of three exons, whereas VHL19 has 160 amino acids and a molecular mass of 19 kDa [16]. Iliopoulos et al. demonstrated that VHL19 is generated from an internal translational start at methionine 54 [16]. Another protein product of the VHL gene, VHL172, which arises from alternative splicing that joins exons one and three while excluding exon two, was also detected [17].
Recently, Lenglet et al. identified transcripts containing a cryptic exon, E1′, located in intron one of the VHL gene, spliced either with exon one or exons two and three [15]. They speculated that a theoretical protein consisting of 193 amino acids could exist, containing 114 amino acids encoded by exon one and 79 amino acids encoded by the cryptic exon, E1′. Their findings were linked to the aberrant retention of this cryptic exon in patients with VHL disease and erythrocytosis.
The reference sequence collection currently displays three mRNA and protein reference variants, which differ in length and exon structure. The three representative isoforms consist of 213, 172, and 193 amino acids residues, respectively [19]. UniProt database describes three isoforms, which are produced by alternative splicing and alternative initiation. Isoform one corresponds to RefSeq isoform one (VHL30 or VHL213) and isoform two corresponds to RefSeq isoform two (VHL172), whereas isoform three corresponds to VHL19 (160 amino acids) and is produced from alternative initiation at methionine 54 [20].
The longest protein isoform has two main protein binding domains, β and α domain, which are preceded by N-terminal acidic disordered domain [21][22]. The β domain is composed of approximately 100 amino acids. This domain is rich in β strands, which form a β-sheet structure, and interacts with hydroxylated HIFs, RNA polymerase II, protein kinase C isoforms, and other proteins [23][24]. The shorter α domain contains binding sites for Elongin-B/C (BC box), Cullin-2 (Cul-2 box), p53, and other proteins [23]. The β domain contains another binding interface, interface C, which is important for VHL localization and binds TBP1 and EEF1A [23].
On the subcellular level, the strongest VHL protein expression was observed in the cytosol, nucleus, mitochondrion and endoplasmic reticulum [25]. Interestingly, Illiopoulus et al. noted that VHL, which is composed of 213 amino acids and corresponds to VHL30, localizes predominantly to cytosol, or is membrane-associated [16]. It was found only in low levels in the nucleus, whereas the 160-amino acid VHL (VHL19) was found in both the nucleus and cytosol. In contrast to the cytosolic membrane-bound VHL30, VHL19 was not associated with cell membranes [16].
RNA sequencing of 27 different normal tissues, from 95 individuals, revealed that VHL protein is ubiquitously expressed in most tissues [26]. However, protein expression studies showed that, despite the relatively high abundance of mRNA in some tissues, the levels of VHL were low or absent, indicating that complex mechanisms govern the mRNA expression, protein synthesis, and/or protein stability of VHL (https://www.proteinatlas.org/ENSG00000134086-VHL/tissue, available from v21.0 proteinatlas.org, accessed on 10 January 2022) [26][27]. This is consistent with general observations in mammalian tissues, where a number of genes exhibited very low correlations between mRNA expression levels and protein staining (Pearson’s r ̴ 0.40) [26][28].
The most important canonical role of VHL, through the EPO-VHL-HIF signaling axis, is its involvement in oxygen sensing and adaptive response to hypoxia (Figure 2) [29][30][31][32][33]. VHL associates with Elongin-B (ELOB) and Elongin-C (ELOC), forming a VBC complex, and, together with Cullin-2 (CUL2) and E3 ubiquitin-protein ligase RBX1 (RBX, Ring-box1), constitutes a functional E3 ubiquitin ligase that specifically recognizes hydroxylated Hypoxia inducible factor (HIF) subunit α, targeting it for proteasome degradation by ubiquitination [34][35][36][37][38][39]. The VHL protein serves as a substrate (e.g., HIF1α) recruitment protein [40][41]. When oxygen levels are normal (normoxic conditions), the two proline residues on the N-terminal (NOOD) and C-terminal (COOD) regions of HIF1α, P402, and P564, respectively, are hydroxylated by the non-heme Fe2+ -oxygen and α-ketogluratate-dependent dioxygenase superfamily of prolyl hydroxylases (PHD1, PHD2, and PHD3) [42][43]. In vitro PHD2 catalyzes the hydroxylation of proline in COOD peptides more efficiently than the NOOD peptide proline, whereas PHD3 specifically hydroxylates only COOD proline [44].
/media/item_content/202203/623bc436cbc96genes-13-00362-g002.png
Figure 2.
Role of VHL in adaptive response to oxygen levels.
The efficiencies of P402 and P564 hydroxylation differ, and when the level of oxygen falls, the hydroxylation of HIF1α prolines is gradually diminished, with P402 more affected than P564 [45][46]. VHL recognizes both hydroxylated prolines with similar binding affinities, resulting in interaction between HIF1α and VBC complex in a 1:2 stoichiometric ratio [47]. HIF1α can therefore bind two VBC complexes or one VBC complex, according to the status of P402 and P564 hydroxylation, at different oxygen levels [45][46][47]. The decrease in VHL targets could lead to gradual increase in HIF1α.
Additionally, in normoxia (normal levels of oxygen), the asparaginyl residue N803 is hydroxylated by factor inhibiting HIF (FIH) or asparaginyl hydroxylase, preventing HIF1α interaction with transcriptional coactivator p300 (EP300) [48][49]. Under low levels of oxygen (hypoxia), HIF1α-specific prolyl and asparaginyl residues are not hydroxylated by PHDs and FIH, respectively. Non-hydroxylated HIF1α subunits can enter the nucleus through specific importins, where they form heterodimeric complexes with Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT, also known as Hypoxia-inducible factor 1, β subunit, HIF1β) [43]. The HIF1α-ARNT complexes act as transcriptional regulators, and bind to consensus 5′-(A/G)CGTG-3′ sequence or HIF ancillary sequences 5′-CAGGT-3′ in hypoxia response elements (HRE), within promoters of several genes involved in adaptive response to hypoxia [42][43].
VHL is also involved in numerous HIF-independent pathways, including protein stabilization [50][51], regulation microtubule stability, and ciliogenesis, as well as stability of the mitotic spindle and chromosomal instability [52][53][54], endocytosis [55], apoptosis [56], protein phosphorylation [57], regulation of gene transcription [58][59][60], regulation of extracellular matrix assembly and tight junctions [61][62][63][64], RNA stability [65][66][67], regulation of senescence [68][69], and, in cytokine signaling pathways, mediating DNA damage response and initiating DNA repair [70] or JAK/STAT signaling [71]. These diverse roles of VHL confirm its implication in several crucial cellular processes, including hypoxia-related cellular adaptations, such as hematopoiesis, metabolic adjustments in oxygen deprived environments, and hypoxia-unrelated mechanisms, such as metabolic rewiring, response to oxidative stress, DNA damage, particularly double-stranded breaks, inflammation, and so on, in the absence or presence of reduced oxygen levels.
Due to its involvement in numerous cellular processes, VHL interacts with several proteins, constituting more or less complex molecular relationships (Figure 3). The occurrence of several VHL isoforms further augments the complexity of VHL biological functions. For example, it has been determined that VHL30, but not VHL19, interacts with tumor suppressor ARF (CDKN2A gene) through the acidic disordered N-terminus. VHL19 lacks the first 53 N-terminal amino acids in this region, and does not interact with ARF [72][73]. ARF promotes interaction between VHL30 and PRMT3, an arginine methyltransferase which can monomethylate or asymmetrically dimethylate several proteins, including p53 and 40S ribosomal protein RPS2 [72]. Methylated p53 arginine residues affect p53 response by influencing the specificity of p53 binding to promoters [74]. Furthermore, VHL isoforms directly interact with p53, which competes for binding to the VHL α region with Elongin-C and ATM, an important cell cycle checkpoint kinase, as well as AURKA, another cell cycle kinase, which is involved in microtubule formation and the regulation of centrosomes, spindles and kinetochores, and centrosomal proteins, e.g., CEP86 [75][76][77]. VHL isoforms, particularly VHL19, have been shown to interact with collagen, fibronectin, and enzymes involved in collagen biosynthesis [72].
Figure 3. STRING network of VHL protein–protein interactions. Settings: Network type, full STRING network; meaning of network edges, confidence (line thickness indicates the strength of data support); active interaction sources, experiments; minimum required interaction score, high confidence (0.700); max number of interactors to show, no more than 20 interactors; organism, Homo sapiens [78].

3. Genetic and Molecular Basis of VHL Disease

The spectra of pathogenic variations in VHL disease is diverse, and the associations between genotypes and phenotypes—the development of specific tumors—are not always predictable [79]. VHL databases, such as VHLdb (http://vhldb.bio.unipd.it/, accessed on 23 December 2021) and the UMD-VHL mutations database (www.umd.be/VHL/, accessed on 23 December 2021), have collected detailed information on over 1600 different pathogenic variations [80]. The COSMIC (https://cancer.sanger.ac.uk/cosmic, accessed on 23 December 2021) database lists more than 1800 entries for genetic variation in VHL gene [81]. Based on the diverse roles VHL exerts in cellular homeostasis in normoxic and hypoxic conditions, the elucidation of the effect of pathogenic variations at the molecular level is a daunting task. Over the years, the efforts of several research groups enabled greater understanding of the molecular mechanisms underlying different types of pathogenic genetic variants.
The most common VHL disease-associated genetic changes include deletions of exons, in-frame insertions and deletions, truncating point mutations, missense mutations, splice-site mutations, and frameshift insertions and deletions, as well as structural variations and even gene fusions [9][80][82][83]. In general, from the perspective of VHL genetic modifications, type 1 is characterized by exonic deletions and truncating mutations, as well as missense mutations, associated with VHL instability and high HIF activity [1][12][83]. In type 2, regardless of the subtype, missense mutations, which have generally been found to retain partial functionality of VHL protein, are predominantly found [1][83]. Furthermore, patients with nonsense or frameshift mutations are at higher risk for the development of RCC and hemangioblastomas. Clinical investigations demonstrated that, in addition to the type of the VHL genetic variant, the disease type is also age dependent, with a penetrance of over 90% by the age of 65 [84].
Studies involving patients with different manifestations of VHL disease, as well as functional studies of genetic aberrations of VHL, have clearly indicated that some aberrations segregate with distinct phenotypes (Table 1). For example, Ong et al. demonstrated that the risk of developing PCC was associated with VHL mutations that change surface amino acids (termed surface mutations), compared to mutations that change amino acids buried deeper within the structure (termed deep mutations), and/or large deletions and truncating (frameshift and nonsense) mutations [9]. Furthermore, the mean age at diagnosis was lower in PCC patients harboring surface mutations than in those carrying other types of mutations in the VHL gene. They also discovered that RCC and retinal hemangioblastoma patients with deleterious mutations were older at the diagnosis of the disease [9]. Hacker et al. determined that p.R167Q and p.D121G type 2B mutations, located in the Elongin-C binding region, probably retained the ability to bind VBC complex proteins Cullin-2 and Elongin-B, as shown in co-immunoprecipitation experiments [85]. Despite the unstable association of proteins that constitute VBC complexes, this research showed that a p.R167Q VHL mutant could ubiquitinylate HIF1α. Buart et al. showed that an R167Q VHL mutation leads to molecular changes related to more pronounced cancer cell stemness and tumor plasticity. VHL-R167Q expressing RCCs are associated with a poor survival [86].
Table 1.
Selected
VHL
genetic variants in VHL disease and their association with phenotype.
Variant Protein Change Codon VHL Type/Phenotype Functional Consequence Reference
c.191G>C R64P 64 Type 2C Increased aPKC JUNB levels; impaired binding to fibronectin. [87][88]
c.194C>T S65L 56 Type 2B Impaired HIF1α binding; impaired HIF2α regulation. [89][90][91]
c.208G>A E70K 70 Type 1 Impaired HIF1α binding. [92][93]
c.233A>G N78S 78 Type 1 Impaired HIF1α regulation. [94][95]
c.239G>A S80N 80 Type 2C No known consequence. [94]
c.245G>C R82P 82 Type 2B Loss of function of VHL. [96]
c.250G>C V84L 84 Type 2C No known consequence. [94]
c.262T>A

c.262T>C		 W88R 88 Hemangio-

Blastoma 1		 No known consequence. [90]
c.269A>T N90I 90 Type 2B Impaired HIF1α regulation. [90][94][97][98]
c.292T>C Y98H 98 Type 2A Impaired HIF1α regulation; defective microtubule stabilization. [87][94]
c.292T>A Y98N 98 Type 2B Impaired HIF1α regulation; impaired GLUT1 suppression. [97]
c.334T>A Y112H 112 Type 2A Impaired HIF1α regulation; decreased VHL stability. [85][99]
c.334T>A Y112N 112 Type 2B Reduced stability of the Vhl-Elongin B/C complex; impaired HIF1α regulation; elevated HIF2α, GLUT1, and cyclin D1 expression in normoxic conditions. [99][100][101]
c.334T>G Y112D 112 Type 2C No known consequence. [94]
c.340G>C G114R 114 Type 2B Reduced stability of the Vhl-Elongin B/C complex. [102]
c.349T>C

c.349T>A		 W117R 117 Type 2B Impaired HIF1α regulation; impaired binding to fibronectin; elevated HIF2α and GLUT1 expression in normoxic conditions. [62][101][103]
c.355T>C

c.357C>G

c.357C>A		 F119L 119 Type 2B Decreased VHL stability; impaired HIF1α regulation. [104]
c.407T>C F136S 136 Type 2B No known consequence. [94]
c.407T>A F136Y 136 Type 2B No known consequence. [94]
c.408T>G F136L 136 Type 2B Decreased VHL stability; impaired HIF1α regulation. [104][105]
c.482G>C R161P 161 Type 2B Reduced stability of the Vhl-Elongin B/C complex; defective microtubule stabilization. [106][107]
c.482G>A R161Q 161 Type 2A; Type 2B Reduced VHL stability. [108]
c.486C>G C162W 162 Hemangio-

Blastoma 1		 Impaired HIF1α regulation. [90][109]
c.499C>T R167W 167 Type 2B Decreased binding to Elongin B/C and Cullin-2; impaired ubiquitination and degradation of ESR1. [62][110]
c.500G>A R167Q 167 Hemangio-

Blastoma 1		 Decreased binding to Elongin C; impaired HIF2α regulation. [90][111][112]
c.562C>G L188V   Type 2C Impaired binding to fibronectin; elevated RWWD3, aPKC, and JUNB levels. [87][88][113][114]
It has been shown that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development [115]. Specific VHL mutations have been associated with defective blood vessel formation. Deletion of VHL alleles and certain type 2B VHL missense mutations resulted in an increased risk for hemangioblastoma and RCC formation. These mutations cause abnormal, often excessive, blood vessel remodeling, and data from a study performed by Arreola et al. suggested that they have different effects on the nature of vascular changes during the development of retinal vasculature [111]. They analyzed embryonic stem cell-derived blood vessels with Vhl−/−, Vhl2B/2B, and WT backgrounds in constructed mouse models with genotypes (i) conditional Vhl-null genotype, (ii) one wild-type Vhl allele and a second mutant Vhl allele with a type 2B p.G518A mutation (equivalent to the VHL p.R167Q protein variation in humans), and (iii) mutant VHL p.G518A allele and conditional deletion of the wild type Vhl allele (mimicking loss of heterozygosity). Non-mutant mouse models were used as controls. The conditional Vhl-null mutation resulted in accelerated arterial vessel maturation, whereas the type 2B Vhl p.G518A mutation caused an increase in vessel-branching complexity and disrupted Notch and Vegf signaling, also demonstrated by increased Vegfa, Hey2, and Notch3 mRNA levels in enriched endothelial cells Vhl2B/2B extracted from embryonic stem (ES) cell cultures. In comparison, the expression profiles of Vegfa and Notch pathway components in Vhl−/− endothelial cells were different, indicating that aberrant Vegfa and Notch signaling pathways in different genetic backgrounds differ, and thus influence the morphological differences in the development of vasculature. Examination of postnatal mouse retinas, obtained at different postnatal development stages, demonstrated that conditional Vhl-null mutation had a profound effect on the reduction of arterial and venous branching in late stages, and very little effect in early stages. Retinal vessels in Vhl heterozygous mice, harboring wild type allele and a type 2B Vhl mutation, showed increased arterial, but not venous, branching, whereas in conditional Vhl homozygous mice, carrying a type 2B Vhl mutation and conditional deletion of second Vhl allele, both arterial and venous branching were observed. Collectively, these results indicated the differential effect of aberrant Vegfa and Notch signaling linked to Vhl missense mutations, or conditional deletion of Vhl, on vascular (dys)morphogenesis [111][116]. These findings could lead to the identification of novel treatment targets in VHL disease, characterized by extensive vascularization due to overproduction of VEGF.
Genotype–phenotype correlations in VHL disease suggest that oxygen-dependent HIF regulation by VHL mutant proteins, as well as HIF-independent VHL functions, modulate the risk of tumor development. It has been established that certain mutations in the VHL gene resulted in a state of pseudohypoxia with elevated levels of HIF proteins, and subsequent activation of HIF-dependent genes, which upregulate angiogenesis, increased cell proliferation and shifted metabolism toward glycolysis, the pentose phosphate pathway, and glutamine-dependent fatty acid biosynthesis, whereas other mutations preferentially affected HIF-independent pathways, without inducing pseudohypoxia [12][87][117]. The HIF signaling pathway is most frequently activated by inactivating mutations of the VHL gene [118]. Abnormally elevated transcriptional activities of the HIF1α and HIF2α genes have been shown to increase tumor survival in solid tumors [119]. Increased hemoglobin concentrations can occasionally occur because of tumor (hyper)production of erythropoietin, as observed in hemangioblastomas, RCC, and PCC [33][118][120][121]. Interestingly, however, despite the fact that elevated HIFs in the background of certain VHL mutations has been associated with erythrocytosis, this condition is not a common feature of VHL disease.
The complexity of phenotype–genotype associations between VHL aberrations and disease is further demonstrated by research data that VHL genetic aberrations follow the so-called continuum model of tumor suppression, which accounts for the zygosity status of genetic change and tissue specificity [108][122]. Indeed, the research performed by Couve et al. indicated that disease phenotype, in the background of specific VHL mutations, can be dependent on the gradient of VHL loss of function, and can show an additive effect in the context of double mutants [108]. Their research resolved intriguing family cases who were classified as having type 2B VHL disease, based on the presence of CNS and retinal hemangioblastomas, RCC, PCC, and pancreatic neuroendocrine tumors. Initially, only heterozygous p.R200W change was found. This change, in hetero- or homozygous form, was firmly associated with normal phenotype and/or erythrocytosis (Chuvash polycythemia), respectively [123][124][125]. Subsequent analyses revealed another change, p.R161Q, located in the same allele together with the p.R200W change, in diseased probands. Protein change p.R161Q was previously associated with type 2A VHL disease, with low risk for the development of RCC. However, the presence of both mutations in the same allele abrogated HIF2α binding, whereas a single p.R161Q mutant showed only partially impaired binding, and p.R200W binding to HIF2α was within the normal range [123][124][125]. Therefore, the simultaneous presence of these two changes in the VHL gene affected the HIF signaling pathway more profoundly and carriers of double mutations were susceptible to type 2B VHL disease.

References

  1. Chou, A.; Toon, C.; Pickett, J.; Gill, A.J. von Hippel-Lindau syndrome. Front. Horm. Res. 2013, 41, 30–49.
  2. Chittiboina, P.; Lonser, R.R. Von Hippel-Lindau disease. Handb. Clin. Neurol. 2015, 132, 139–156.
  3. Lonser, R.R.; Glenn, G.M.; Walther, M.; Chew, E.Y.; Libutti, S.K.; Linehan, W.M.; Oldfield, E.H. von Hippel-Lindau disease. Lancet 2003, 361, 2059–2067.
  4. Ding, X.; Zhang, C.; Frerich, J.M.; Germanwala, A.; Yang, C.; Lonser, R.R.; Mao, Y.; Zhuang, Z.; Zhang, M. De novo VHL germline mutation detected in a patient with mild clinical phenotype of von Hippel-Lindau disease. J. Neurosurg. 2014, 121, 384–386.
  5. Glasker, S.; Sohn, T.S.; Okamoto, H.; Li, J.; Lonser, R.R.; Oldfield, E.H.; Vortmeyer, A.O.; Zhuang, Z. Second hit deletion size in von Hippel-Lindau disease. Ann. Neurol. 2006, 59, 105–110.
  6. Murro, V.; Lippera, M.; Mucciolo, D.P.; Canu, L.; Ercolino, T.; De Filpo, G.; Giorgio, D.; Traficante, G.; Sodi, A.; Virgili, G.; et al. Outcome and genetic analysis of patients affected by retinal capillary hemangioblastoma in von Hippel Lindau syndrome. Mol. Vis. 2021, 27, 542–554.
  7. Richards, F.M.; Payne, S.J.; Zbar, B.; Affara, N.A.; Ferguson-Smith, M.A.; Maher, E.R. Molecular analysis of de novo germline mutations in the von Hippel-Lindau disease gene. Hum. Mol. Genet. 1995, 4, 2139–2143.
  8. Ang, S.O.; Chen, H.; Hirota, K.; Gordeuk, V.R.; Jelinek, J.; Guan, Y.; Liu, E.; Sergueeva, A.I.; Miasnikova, G.Y.; Mole, D.; et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat. Genet. 2002, 32, 614–621.
  9. Ong, K.R.; Woodward, E.R.; Killick, P.; Lim, C.; Macdonald, F.; Maher, E.R. Genotype-phenotype correlations in von Hippel-Lindau disease. Hum. Mutat. 2007, 28, 143–149.
  10. Woodward, E.R.; Eng, C.; McMahon, R.; Voutilainen, R.; Affara, N.A.; Ponder, B.A.; Maher, E.R. Genetic predisposition to phaeochromocytoma: Analysis of candidate genes GDNF, RET and VHL. Hum. Mol. Genet. 1997, 6, 1051–1056.
  11. Bento, C.; Percy, M.J.; Gardie, B.; Maia, T.M.; van Wijk, R.; Perrotta, S.; Della Ragione, F.; Almeida, H.; Rossi, C.; Girodon, F.; et al. Genetic basis of congenital erythrocytosis: Mutation update and online databases. Hum. Mutat. 2014, 35, 15–26.
  12. Aronow, M.E.; Wiley, H.E.; Gaudric, A.; Krivosic, V.; Gorin, M.B.; Shields, C.L.; Shields, J.A.; Jonasch, E.W.; Singh, A.D.; Chew, E.Y. VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects. Retina 2019, 39, 2243–2253.
  13. Latif, F.; Tory, K.; Gnarra, J.; Yao, M.; Duh, F.M.; Orcutt, M.L.; Stackhouse, T.; Kuzmin, I.; Modi, W.; Geil, L.; et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993, 260, 1317–1320.
  14. Blankenship, C.; Naglich, J.G.; Whaley, J.M.; Seizinger, B.; Kley, N. Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene 1999, 18, 1529–1535.
  15. Lenglet, M.; Robriquet, F.; Schwarz, K.; Camps, C.; Couturier, A.; Hoogewijs, D.; Buffet, A.; Knight, S.J.L.; Gad, S.; Couve, S.; et al. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease. Blood 2018, 132, 469–483.
  16. Iliopoulos, O.; Ohh, M.; Kaelin, W.G., Jr. pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc. Natl. Acad. Sci. USA 1998, 95, 11661–11666.
  17. Richards, F.M.; Schofield, P.N.; Fleming, S.; Maher, E.R. Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis. Hum. Mol. Genet. 1996, 5, 639–644.
  18. Schoenfeld, A.; Davidowitz, E.J.; Burk, R.D. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc. Natl. Acad. Sci. USA 1998, 95, 8817–8822.
  19. O’Leary, N.A.; Wright, M.W.; Brister, J.R.; Ciufo, S.; Haddad, D.; McVeigh, R.; Rajput, B.; Robbertse, B.; Smith-White, B.; Ako-Adjei, D.; et al. Reference sequence (RefSeq) database at NCBI: Current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 2016, 44, D733–D745.
  20. UniProt, C. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res. 2021, 49, D480–D489.
  21. Min, J.H.; Yang, H.; Ivan, M.; Gertler, F.; Kaelin, W.G., Jr.; Pavletich, N.P. Structure of an HIF-1alpha -pVHL complex: Hydroxyproline recognition in signaling. Science 2002, 296, 1886–1889.
  22. Stebbins, C.E.; Kaelin, W.G., Jr.; Pavletich, N.P. Structure of the VHL-ElonginC-ElonginB complex: Implications for VHL tumor suppressor function. Science 1999, 284, 455–461.
  23. Leonardi, E.; Murgia, A.; Tosatto, S.C. Adding structural information to the von Hippel-Lindau (VHL) tumor suppressor interaction network. FEBS Lett. 2009, 583, 3704–3710.
  24. Okuda, H.; Hirai, S.; Takaki, Y.; Kamada, M.; Baba, M.; Sakai, N.; Kishida, T.; Kaneko, S.; Yao, M.; Ohno, S.; et al. Direct interaction of the β-domain of VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes. Biochem. Biophys. Res. Commun. 1999, 263, 491–497.
  25. Stelzer, G.; Rosen, N.; Plaschkes, I.; Zimmerman, S.; Twik, M.; Fishilevich, S.; Stein, T.I.; Nudel, R.; Lieder, I.; Mazor, Y.; et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr. Protoc. Bioinform. 2016, 54, 1–30.
  26. Fagerberg, L.; Hallstrom, B.M.; Oksvold, P.; Kampf, C.; Djureinovic, D.; Odeberg, J.; Habuka, M.; Tahmasebpoor, S.; Danielsson, A.; Edlund, K.; et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell Proteom. 2014, 13, 397–406.
  27. Wang, D.; Eraslan, B.; Wieland, T.; Hallstrom, B.; Hopf, T.; Zolg, D.P.; Zecha, J.; Asplund, A.; Li, L.H.; Meng, C.; et al. A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Mol. Syst. Biol. 2019, 15, e8503.
  28. Perl, K.; Ushakov, K.; Pozniak, Y.; Yizhar-Barnea, O.; Bhonker, Y.; Shivatzki, S.; Geiger, T.; Avraham, K.B.; Shamir, R. Reduced changes in protein compared to mRNA levels across non-proliferating tissues. BMC Genom. 2017, 18, 305.
  29. Hsu, T. Complex cellular functions of the von Hippel-Lindau tumor suppressor gene: Insights from model organisms. Oncogene 2012, 31, 2247–2257.
  30. Li, T.; Mao, C.; Wang, X.; Shi, Y.; Tao, Y. Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation. J. Exp. Clin. Cancer Res. 2020, 39, 224.
  31. Liao, C.; Zhang, Q. Understanding the Oxygen-Sensing Pathway and Its Therapeutic Implications in Diseases. Am. J. Pathol. 2020, 190, 1584–1595.
  32. Tomc, J.; Debeljak, N. Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis. Int. J. Mol. Sci. 2021, 22, 7074.
  33. Kaelin, W.G., Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat. Rev. Cancer 2002, 2, 673–682.
  34. Iliopoulos, O.; Kibel, A.; Gray, S.; Kaelin, W.G., Jr. Tumour suppression by the human von Hippel-Lindau gene product. Nat. Med. 1995, 1, 822–826.
  35. Kibel, A.; Iliopoulos, O.; DeCaprio, J.A.; Kaelin, W.G., Jr. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 1995, 269, 1444–1446.
  36. Wang, G.L.; Semenza, G.L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 1995, 270, 1230–1237.
  37. Iliopoulos, O.; Levy, A.P.; Jiang, C.; Kaelin, W.G., Jr.; Goldberg, M.A. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc. Natl. Acad. Sci. USA 1996, 93, 10595–10599.
  38. Lonergan, K.M.; Iliopoulos, O.; Ohh, M.; Kamura, T.; Conaway, R.C.; Conaway, J.W.; Kaelin, W.G., Jr. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol. Cell Biol. 1998, 18, 732–741.
  39. Maxwell, P.H.; Wiesener, M.S.; Chang, G.W.; Clifford, S.C.; Vaux, E.C.; Cockman, M.E.; Wykoff, C.C.; Pugh, C.W.; Maher, E.R.; Ratcliffe, P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999, 399, 271–275.
  40. Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J.M.; Lane, W.S.; Kaelin, W.G., Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science 2001, 292, 464–468.
  41. Jaakkola, P.; Mole, D.R.; Tian, Y.M.; Wilson, M.I.; Gielbert, J.; Gaskell, S.J.; von Kriegsheim, A.; Hebestreit, H.F.; Mukherji, M.; Schofield, C.J.; et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001, 292, 468–472.
  42. Dengler, V.L.; Galbraith, M.; Espinosa, J.M. Transcriptional regulation by hypoxia inducible factors. Crit. Rev. Biochem. Mol. Biol. 2014, 49, 1–15.
  43. Metzen, E.; Ratcliffe, P.J. HIF hydroxylation and cellular oxygen sensing. Biol. Chem. 2004, 385, 223–230.
  44. Hirsila, M.; Koivunen, P.; Gunzler, V.; Kivirikko, K.I.; Myllyharju, J. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem. 2003, 278, 30772–30780.
  45. Chan, D.A.; Sutphin, P.D.; Yen, S.E.; Giaccia, A.J. Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1 α. Mol. Cell Biol. 2005, 25, 6415–6426.
  46. Tian, Y.M.; Yeoh, K.K.; Lee, M.K.; Eriksson, T.; Kessler, B.M.; Kramer, H.B.; Edelmann, M.J.; Willam, C.; Pugh, C.W.; Schofield, C.J.; et al. Differential sensitivity of hypoxia inducible factor hydroxylation sites to hypoxia and hydroxylase inhibitors. J. Biol. Chem. 2011, 286, 13041–13051.
  47. He, W.; Batty-Stuart, S.; Lee, J.E.; Ohh, M. HIF-1alpha Hydroxyprolines Modulate Oxygen-Dependent Protein Stability Via Single VHL Interface With Comparable Effect on Ubiquitination Rate. J. Mol. Biol. 2021, 433, 167244.
  48. Hewitson, K.S.; McNeill, L.A.; Riordan, M.V.; Tian, Y.M.; Bullock, A.N.; Welford, R.W.; Elkins, J.M.; Oldham, N.J.; Bhattacharya, S.; Gleadle, J.M.; et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem. 2002, 277, 26351–26355.
  49. Lando, D.; Peet, D.J.; Whelan, D.A.; Gorman, J.J.; Whitelaw, M.L. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 2002, 295, 858–861.
  50. Zhou, M.I.; Wang, H.; Ross, J.J.; Kuzmin, I.; Xu, C.; Cohen, H.T. The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J. Biol. Chem. 2002, 277, 39887–39898.
  51. Zeng, L.; Bai, M.; Mittal, A.K.; El-Jouni, W.; Zhou, J.; Cohen, D.M.; Zhou, M.I.; Cohen, H.T. Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. Cancer Res. 2013, 73, 5371–5380.
  52. Schermer, B.; Ghenoiu, C.; Bartram, M.; Muller, R.U.; Kotsis, F.; Hohne, M.; Kuhn, W.; Rapka, M.; Nitschke, R.; Zentgraf, H.; et al. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J. Cell Biol. 2006, 175, 547–554.
  53. Frew, I.J.; Smole, Z.; Thoma, C.R.; Krek, W. Genetic deletion of the long isoform of the von Hippel-Lindau tumour suppressor gene product alters microtubule dynamics. Eur. J. Cancer 2013, 49, 2433–2440.
  54. Thoma, C.R.; Toso, A.; Gutbrodt, K.L.; Reggi, S.P.; Frew, I.J.; Schraml, P.; Hergovich, A.; Moch, H.; Meraldi, P.; Krek, W. VHL loss causes spindle misorientation and chromosome instability. Nat. Cell Biol. 2009, 11, 994–1001.
  55. Hsu, T.; Adereth, Y.; Kose, N.; Dammai, V. Endocytic function of von Hippel-Lindau tumor suppressor protein regulates surface localization of fibroblast growth factor receptor 1 and cell motility. J. Biol. Chem. 2006, 281, 12069–12080.
  56. Jinesh, G.G.; Kamat, A.M. RalBP1 and p19-VHL play an oncogenic role, and p30-VHL plays a tumor suppressor role during the blebbishield emergency program. Cell Death Discov. 2017, 3, 17023.
  57. Yang, H.; Minamishima, Y.A.; Yan, Q.; Schlisio, S.; Ebert, B.L.; Zhang, X.; Zhang, L.; Kim, W.Y.; Olumi, A.F.; Kaelin, W.G., Jr. pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2. Mol. Cell. 2007, 28, 15–27.
  58. Kuznetsova, A.V.; Meller, J.; Schnell, P.O.; Nash, J.A.; Ignacak, M.L.; Sanchez, Y.; Conaway, J.W.; Conaway, R.C.; Czyzyk-Krzeska, M.F. von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination. Proc. Natl. Acad. Sci. USA 2003, 100, 2706–2711.
  59. Mikhaylova, O.; Ignacak, M.L.; Barankiewicz, T.J.; Harbaugh, S.V.; Yi, Y.; Maxwell, P.H.; Schneider, M.; Van Geyte, K.; Carmeliet, P.; Revelo, M.P.; et al. The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Mol. Cell Biol. 2008, 28, 2701–2717.
  60. Na, X.; Duan, H.O.; Messing, E.M.; Schoen, S.R.; Ryan, C.K.; di Sant’Agnese, P.A.; Golemis, E.A.; Wu, G. Identification of the RNA polymerase II subunit hsRPB7 as a novel target of the von Hippel-Lindau protein. EMBO J. 2003, 22, 4249–4259.
  61. Calzada, M.J.; Esteban, M.A.; Feijoo-Cuaresma, M.; Castellanos, M.C.; Naranjo-Suarez, S.; Temes, E.; Mendez, F.; Yanez-Mo, M.; Ohh, M.; Landazuri, M.O. von Hippel-Lindau tumor suppressor protein regulates the assembly of intercellular junctions in renal cancer cells through hypoxia-inducible factor-independent mechanisms. Cancer Res. 2006, 66, 1553–1560.
  62. Ohh, M.; Yauch, R.L.; Lonergan, K.M.; Whaley, J.M.; Stemmer-Rachamimov, A.O.; Louis, D.N.; Gavin, B.J.; Kley, N.; Kaelin, W.G., Jr.; Iliopoulos, O. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol. Cell 1998, 1, 959–968.
  63. Sevilla-Montero, J.; Bienes-Martinez, R.; Labrousse-Arias, D.; Fuertes-Yebra, E.; Ordonez, A.; Calzada, M.J. pVHL-mediated regulation of the anti-angiogenic protein thrombospondin-1 decreases migration of Clear Cell Renal Carcinoma Cell Lines. Sci. Rep. 2020, 10, 1175.
  64. Tang, N.; Mack, F.; Haase, V.H.; Simon, M.C.; Johnson, R.S. pVHL function is essential for endothelial extracellular matrix deposition. Mol. Cell Biol. 2006, 26, 2519–2530.
  65. Danilin, S.; Sourbier, C.; Thomas, L.; Rothhut, S.; Lindner, V.; Helwig, J.J.; Jacqmin, D.; Lang, H.; Massfelder, T. von Hippel-Lindau tumor suppressor gene-dependent mRNA stabilization of the survival factor parathyroid hormone-related protein in human renal cell carcinoma by the RNA-binding protein HuR. Carcinogenesis 2009, 30, 387–396.
  66. Galban, S.; Martindale, J.L.; Mazan-Mamczarz, K.; Lopez de Silanes, I.; Fan, J.; Wang, W.; Decker, J.; Gorospe, M. Influence of the RNA-binding protein HuR in pVHL-regulated p53 expression in renal carcinoma cells. Mol. Cell Biol. 2003, 23, 7083–7095.
  67. Xin, H.; Brown, J.A.; Gong, C.; Fan, H.; Brewer, G.; Gnarra, J.R. Association of the von Hippel-Lindau protein with AUF1 and posttranscriptional regulation of VEGFA mRNA. Mol. Cancer Res. 2012, 10, 108–120.
  68. Kim, W.Y.; Sharpless, N.E. VHL inactivation: A new road to senescence. Cancer Cell 2008, 13, 295–297.
  69. Young, A.P.; Schlisio, S.; Minamishima, Y.A.; Zhang, Q.; Li, L.; Grisanzio, C.; Signoretti, S.; Kaelin, W.G., Jr. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat. Cell Biol. 2008, 10, 361–369.
  70. Metcalf, J.L.; Bradshaw, P.S.; Komosa, M.; Greer, S.N.; Stephen Meyn, M.; Ohh, M. K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair. Oncogene 2014, 33, 1055–1065.
  71. Russell, R.C.; Sufan, R.I.; Zhou, B.; Heir, P.; Bunda, S.; Sybingco, S.S.; Greer, S.N.; Roche, O.; Heathcote, S.A.; Chow, V.W.; et al. Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia. Nat. Med. 2011, 17, 845–853.
  72. Lai, Y.; Song, M.; Hakala, K.; Weintraub, S.T.; Shiio, Y. Proteomic dissection of the von Hippel-Lindau (VHL) interactome. J. Proteome Res. 2011, 10, 5175–5182.
  73. Minervini, G.; Mazzotta, G.M.; Masiero, A.; Sartori, E.; Corra, S.; Potenza, E.; Costa, R.; Tosatto, S.C. Isoform-specific interactions of the von Hippel-Lindau tumor suppressor protein. Sci. Rep. 2015, 5, 12605.
  74. Jansson, M.; Durant, S.T.; Cho, E.C.; Sheahan, S.; Edelmann, M.; Kessler, B.; La Thangue, N.B. Arginine methylation regulates the p53 response. Nat. Cell Biol. 2008, 10, 1431–1439.
  75. Roe, J.S.; Kim, H.; Lee, S.M.; Kim, S.T.; Cho, E.J.; Youn, H.D. p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol. Cell 2006, 22, 395–405.
  76. Kong, L.; Yin, H.; Yuan, L. Centrosomal MCM7 strengthens the Cep68-VHL interaction and excessive MCM7 leads to centrosome splitting resulting from increase in Cep68 ubiquitination and proteasomal degradation. Biochem. Biophys. Res. Commun. 2017, 489, 497–502.
  77. Hasanov, E.; Chen, G.; Chowdhury, P.; Weldon, J.; Ding, Z.; Jonasch, E.; Sen, S.; Walker, C.L.; Dere, R. Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL. Oncogene 2017, 36, 3450–3463.
  78. Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; et al. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019, 47, D607–D613.
  79. Choi, H.; Kim, K.J.; Hong, N.; Shin, S.; Choi, J.R.; Kang, S.W.; Lee, S.T.; Rhee, Y. Genetic Analysis and Clinical Characteristics of Hereditary Pheochromocytoma and Paraganglioma Syndrome in Korean Population. Endocrinol. Metab. 2020, 35, 858–872.
  80. Tabaro, F.; Minervini, G.; Sundus, F.; Quaglia, F.; Leonardi, E.; Piovesan, D.; Tosatto, S.C. VHLdb: A database of von Hippel-Lindau protein interactors and mutations. Sci. Rep. 2016, 6, 31128.
  81. Tate, J.G.; Bamford, S.; Jubb, H.C.; Sondka, Z.; Beare, D.M.; Bindal, N.; Boutselakis, H.; Cole, C.G.; Creatore, C.; Dawson, E.; et al. COSMIC: The Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2019, 47, D941–D947.
  82. Cerami, E.; Gao, J.; Dogrusoz, U.; Gross, B.E.; Sumer, S.O.; Aksoy, B.A.; Jacobsen, A.; Byrne, C.J.; Heuer, M.L.; Larsson, E.; et al. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012, 2, 401–404.
  83. Maher, E.R.; Sandford, R.N. von Hippel-Lindau Disease: An Update. Curr. Genet. Med. Rep. 2019, 7, 227–235.
  84. Crespigio, J.; Berbel, L.C.L.; Dias, M.A.; Berbel, R.F.; Pereira, S.S.; Pignatelli, D.; Mazzuco, T.L. Von Hippel-Lindau disease: A single gene, several hereditary tumors. J. Endocrinol. Investig. 2018, 41, 21–31.
  85. Hacker, K.E.; Lee, C.M.; Rathmell, W.K. VHL type 2B mutations retain VBC complex form and function. PLoS ONE 2008, 3, e3801.
  86. Buart, S.; Terry, S.; Diop, M.K.; Dessen, P.; Couve, S.; Abdou, A.; Adam, J.; Thiery, J.; Savagner, P.; Chouaib, S. The Most Common VHL Point Mutation R167Q in Hereditary VHL Disease Interferes with Cell Plasticity Regulation. Cancers 2021, 13, 3897.
  87. Hoffman, M.A.; Ohh, M.; Yang, H.; Klco, J.M.; Ivan, M.; Kaelin, W.G., Jr. von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum. Mol. Genet. 2001, 10, 1019–1027.
  88. Lee, S.; Nakamura, E.; Yang, H.; Wei, W.; Linggi, M.S.; Sajan, M.P.; Farese, R.V.; Freeman, R.S.; Carter, B.D.; Kaelin, W.G., Jr.; et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer. Cancer Cell 2005, 8, 155–167.
  89. Guo, K.; Wei, Y.; Wang, Z.; Zhang, X.; Zhang, X.; Liu, X.; Wu, W.; Wu, Z.; Zhang, L.; Cui, C.P. Deubiquitylase OTUD6B stabilizes the mutated pVHL and suppresses cell migration in clear cell renal cell carcinoma. Cell Death Dis. 2022, 13, 97.
  90. Hong, B.; Ma, K.; Zhou, J.; Zhang, J.; Wang, J.; Liu, S.; Zhang, Z.; Cai, L.; Zhang, N.; Gong, K. Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease. Front. Genet. 2019, 10, 867.
  91. Miller, F.; Kentsis, A.; Osman, R.; Pan, Z.Q. Inactivation of VHL by tumorigenic mutations that disrupt dynamic coupling of the pVHL.hypoxia-inducible transcription factor-1alpha complex. J. Biol. Chem. 2005, 280, 7985–7996.
  92. Forman, J.R.; Worth, C.L.; Bickerton, G.R.; Eisen, T.G.; Blundell, T.L. Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis. Proteins 2009, 77, 84–96.
  93. Hwang, S.; Ku, C.R.; Lee, J.I.; Hur, K.Y.; Lee, M.S.; Lee, C.H.; Koo, K.Y.; Lee, J.S.; Rhee, Y. Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease. J. Hum. Genet. 2014, 59, 488–493.
  94. Hergovich, A.; Lisztwan, J.; Barry, R.; Ballschmieter, P.; Krek, W. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat. Cell Biol. 2003, 5, 64–70.
  95. Lin, G.; Zhao, Y.; Zhang, Z.; Zhang, H. Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel-Lindau disease pedigrees. Exp. Ther. Med. 2020, 20, 1237–1244.
  96. Li, Z.; Na, X.; Wang, D.; Schoen, S.R.; Messing, E.M.; Wu, G. Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein. J. Biol. Chem. 2002, 277, 4656–4662.
  97. Cockman, M.E.; Masson, N.; Mole, D.R.; Jaakkola, P.; Chang, G.W.; Clifford, S.C.; Maher, E.R.; Pugh, C.W.; Ratcliffe, P.J.; Maxwell, P.H. Hypoxia inducible factor-α binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J. Biol. Chem. 2000, 275, 25733–25741.
  98. Vaux, E.C.; Wood, S.M.; Cockman, M.E.; Nicholls, L.G.; Yeates, K.M.; Pugh, C.W.; Maxwell, P.H.; Ratcliffe, P.J. Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel-Lindau tumor suppressor. J. Biol. Chem. 2001, 276, 44323–44330.
  99. Knauth, K.; Bex, C.; Jemth, P.; Buchberger, A. Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1alpha interactions. Oncogene 2006, 25, 370–377.
  100. Chung, J.; Roberts, A.M.; Chow, J.; Coady-Osberg, N.; Ohh, M. Homotypic association between tumour-associated VHL proteins leads to the restoration of HIF pathway. Oncogene 2006, 25, 3079–3083.
  101. Li, L.; Zhang, L.; Zhang, X.; Yan, Q.; Minamishima, Y.A.; Olumi, A.F.; Mao, M.; Bartz, S.; Kaelin, W.G., Jr. Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol. Cell Biol. 2007, 27, 5381–5392.
  102. Feldman, D.E.; Spiess, C.; Howard, D.E.; Frydman, J. Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding. Mol. Cell 2003, 12, 1213–1224.
  103. Hansen, W.J.; Ohh, M.; Moslehi, J.; Kondo, K.; Kaelin, W.G.; Welch, W.J. Diverse effects of mutations in exon II of the von Hippel-Lindau (VHL) tumor suppressor gene on the interaction of pVHL with the cytosolic chaperonin and pVHL-dependent ubiquitin ligase activity. Mol. Cell Biol. 2002, 22, 1947–1960.
  104. Shmueli, M.D.; Schnaider, L.; Rosenblum, D.; Herzog, G.; Gazit, E.; Segal, D. Structural insights into the folding defects of oncogenic pVHL lead to correction of its function in vitro. PLoS ONE 2013, 8, e66333.
  105. Shmueli, M.D.; Levy-Kanfo, L.; Haj, E.; Schoenfeld, A.R.; Gazit, E.; Segal, D. Arginine refolds, stabilizes, and restores function of mutant pVHL proteins in animal model of the VHL cancer syndrome. Oncogene 2019, 38, 1038–1049.
  106. Ohh, M.; Takagi, Y.; Aso, T.; Stebbins, C.E.; Pavletich, N.P.; Zbar, B.; Conaway, R.C.; Conaway, J.W.; Kaelin, W.G., Jr. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J. Clin. Investig. 1999, 104, 1583–1591.
  107. Thoma, C.R.; Matov, A.; Gutbrodt, K.L.; Hoerner, C.R.; Smole, Z.; Krek, W.; Danuser, G. Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability. J. Cell Biol. 2010, 190, 991–1003.
  108. Couve, S.; Ladroue, C.; Laine, E.; Mahtouk, K.; Guegan, J.; Gad, S.; Le Jeune, H.; Le Gentil, M.; Nuel, G.; Kim, W.Y.; et al. Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis. Cancer Res. 2014, 74, 6554–6564.
  109. Iturrioz, X.; Parker, P.J. PKCzetaII is a target for degradation through the tumour suppressor protein pVHL. FEBS Lett. 2007, 581, 1397–1402.
  110. Jung, Y.S.; Lee, S.J.; Yoon, M.H.; Ha, N.C.; Park, B.J. Estrogen receptor α is a novel target of the Von Hippel-Lindau protein and is responsible for the proliferation of VHL-deficient cells under hypoxic conditions. Cell Cycle 2012, 11, 4462–4473.
  111. Arreola, A.; Payne, L.B.; Julian, M.H.; de Cubas, A.A.; Daniels, A.B.; Taylor, S.; Zhao, H.; Darden, J.; Bautch, V.L.; Rathmell, W.K.; et al. Von Hippel-Lindau mutations disrupt vascular patterning and maturation via Notch. JCI Insight 2018, 3, e92193.
  112. Rathmell, W.K.; Hickey, M.M.; Bezman, N.A.; Chmielecki, C.A.; Carraway, N.C.; Simon, M.C. In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations. Cancer Res. 2004, 64, 8595–8603.
  113. Kurban, G.; Hudon, V.; Duplan, E.; Ohh, M.; Pause, A. Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res. 2006, 66, 1313–1319.
  114. Tedesco, L.; Elguero, B.; Pacin, D.G.; Senin, S.; Pollak, C.; Garcia Marchinena, P.A.; Jurado, A.M.; Isola, M.; Labanca, M.J.; Palazzo, M.; et al. von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME. Cell Death Dis. 2019, 10, 266.
  115. de Rojas, P.I.; Albinana, V.; Taranets, L.; Recio-Poveda, L.; Cuesta, A.M.; Popov, N.; Kronenberger, T.; Botella, L.M. The Endothelial Landscape and Its Role in Von Hippel-Lindau Disease. Cells 2021, 10, 2313.
  116. Glasker, S.; Vergauwen, E.; Koch, C.A.; Kutikov, A.; Vortmeyer, A.O. Von Hippel-Lindau Disease: Current Challenges and Future Prospects. Onco Targets Ther. 2020, 13, 5669–5690.
  117. Creighton, C.J.; Morgan, M.; Gunaratne, P.H.; Wheeler, D.A.; Gibbs, R.A.; Gordon Robertson, A.; Chu, A.; Beroukhim, R.; Cibulskis, K.; Signoretti, S.; et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013, 499, 43–49.
  118. Krieg, M.; Marti, H.H.; Plate, K.H. Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Blood 1998, 92, 3388–3393.
  119. Fallah, J.; Rini, B.I. HIF Inhibitors: Status of Current Clinical Development. Curr. Oncol. Rep. 2019, 21, 6.
  120. Gordeuk, V.R.; Prchal, J.T. Vascular complications in Chuvash polycythemia. Semin. Thromb. Hemost. 2006, 32, 289–294.
  121. Kaelin, W.G., Jr. The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem. Biophys. Res. Commun. 2005, 338, 627–638.
  122. Berger, A.H.; Knudson, A.G.; Pandolfi, P.P. A continuum model for tumour suppression. Nature 2011, 476, 163–169.
  123. Ang, S.O.; Chen, H.; Gordeuk, V.R.; Sergueeva, A.I.; Polyakova, L.A.; Miasnikova, G.Y.; Kralovics, R.; Stockton, D.W.; Prchal, J.T. Endemic polycythemia in Russia: Mutation in the VHL gene. Blood Cells Mol. Dis. 2002, 28, 57–62.
  124. Polyakova, L.A. Familial erythrocytosis among inhabitants of the Chuvash ASSR. Probl. Gematol. Pereliv. Krovi 1974, 10, 30–36.
  125. Sergeyeva, A.; Gordeuk, V.R.; Tokarev, Y.N.; Sokol, L.; Prchal, J.F.; Prchal, J.T. Congenital polycythemia in Chuvashia. Blood 1997, 89, 2148–2154.
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