von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome passed down in an autosomal-dominant fashion. It is named after physicians Eugen von Hippel and Arvid Lindau, who first described families with a genetic predisposition to retinal and central nervous system (CNS) hemangioblastoma, respectively (Lindau, 1904; Davison et al., 1936; Hippel, 1904). VHL disease is rare, afflicting approximately 1 in 35,000 people (Neumann and Wiestler, 1991; Maher et al., 1991). In addition to the retinal and central nervous system hemangioblastoma, other cardinal features of VHL disease include clear-cell renal cell carcinoma (RCC), the commonest form of kidney cancer, and pheochromocytoma, a neuroendocrine tumor derived from adrenal chromaffin cells, in addition to pancreatic, renal and epididymal cysts, endolymphatic sac tumors, and polycythemia (Lindau, 1904 ; Davison et al., 1936; Hippel, 1904).

In 1993, the VHL gene was cloned and mutations of the locus were determined to be causative of VHL disease (Latif et al., 1993). By sequencing the VHL gene in various families afflicted with VHL disease, a complex genotype-phenotype correlation emerged. First, VHL disease is broadly separated into two types based on the propensity of developing pheochromocytoma where Type 1 patients have a low risk while Type 2 patients have a high risk of pheochromocytoma. Type 1 patients also develop hemangioblastoma and RCC. Type 2 disease is further stratified into Type 2a (high risk of hemangioblastoma with low risk of RCC), Type 2b (high risk of hemangioblastoma and RCC), and Type 2c (only pheochromocytoma without the other disease manifestations). Moreover, VHL mutations have been found to be causative of autosomal-recessive familial polycythemia, which is sometimes referred to as Type 3 VHL disease (Table 1). While polycythemia refers to a nonspecific increase in the volume percentage of red blood cells in the blood, also known as hematocrit, this increase in VHL disease and other pseudohypoxic diseases is known to result from excess red blood cell production, termed erythrocytosis. VHL disease Type 1 and 2 are inherited in an autosomal-dominant manner, which predisposes an individual to developing cancer upon the loss of the remaining wild-type allele. In other words, there must be a loss of heterozygosity resulting either from large deletions, mitotic recombination, or hypermethylation of the wild-type allele in a susceptible cell for a tumor to form (Prowse et al., 1997). However, to develop polycythemia associated with VHL disease Type 3, an individual must inherit two mutated VHL alleles, meaning it is an autosomal-recessive disease.

The protein product of VHL is termed pVHL, which forms an E3 ubiquitin ligase complex (pVHL-E3) with elongin B, elongin C, cullin 2, and Rbx1 (Kamura et al., 1999; Cardote et al., 2017). pVHL serves as the substrate-conferring component of the pVHL-E3 ligase, an integral component in the metazoan oxygen-sensing pathway (Figure 1). The best-characterized substrates of the pVHL-E3 ligase remain the hypoxia-inducible factor (HIF) alpha subunit paralogs HIF1α, HIF2α, and HIF3α. HIFs are heterodimeric transcription factors consisting of an oxygen-labile α subunit and a constitutively expressed β subunit (Figure 1). In the presence of sufficient oxygen, prolyl hydroxylase (PHD) enzymes hydroxylate the conserved proline residues on HIFα, which results in pVHL binding to HIFα and subsequent polyubiquitylation leading to 26 S proteasomal-mediated degradation of HIFα (Figure 1; Epstein et al., 2001; Jaakkola et al., 2001; Ivan et al., 2001; Bruick and McKnight, 2001). Under hypoxic conditions, HIFα remains unhydroxylated, escapes recognition via pVHL, and is therefore not degraded. This pool of stabilized HIFα is able to both dimerize with HIFβ and translocate to the nucleus where it transcriptionally regulates many genes involved in the adaptive hypoxic response including metabolic enzymes, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) (Figure 1; Jiang et al., 1996).

Figure 1

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Although the connection between HIF deregulation and VHL disease was readily appreciated, a hypothesis emerged that the complicated genotype-phenotype correlation in VHL disease could not be fully explained by HIF dysregulation alone. This argument implies that pVHL carries out other cellular functions and/or targets other substrates for ubiquitin-mediated degradation that are integral to the manifestation of the full spectrum VHL disease phenotypes. Here, we revisit the available and emerging evidence surrounding the relationship between HIF and VHL disease and propose that HIF dysregulation is the driver of the genotype-phenotype correlation in VHL disease.

The strongest evidence for additional non-HIFα related functions came from early biochemical studies of Type 2c pVHL mutants. Type 2c VHL disease is associated with pheochromocytoma without other disease phenotypes, and several Type 2c pVHL mutants were found to promote HIFα polyubiquitylation at seemingly wild-type levels (Hoffman et al., 2001; Clifford et al., 2001). A second peculiarity centered on Type 1 VHL disease. Despite Type 1 disease driven by mutations predicted to profoundly inactivate pVHL, including nonsense, frameshift and splicing mutations, these patients do not develop pheochromocytoma (Stebbins et al., 1999; Chen et al., 1995; Crossey et al., 1995; Stolle et al., 1998). Thus, pheochromocytoma seemed uncoupled from HIF stabilization (more on this later).

To better understand VHL disease, researchers searched for other targets and/or functions of pVHL. Notably, pVHL has been linked to the regulation of extracellular matrix proteins collagen and fibronectin (Ohh et al., 1998; Kurban et al., 1998a; Grosfeld et al., 2007; Stickle et al., 2004; Kurban et al., 1998b), microtubules (Thoma et al., 2009; Hergovich et al., 2006; Hergovich et al., 2003), primary cilia (Montani et al., 2010; Esteban et al., 2006), NFκB (Cummins et al., 2006; Yang et al., 2007), Human Antigen R (HuR) (Danilin et al., 2009; Massfelder et al., 2004), AKT kinase (Guo et al., 2016), p14/ARF (Minervini et al., 2015; Lai et al., 2011), and ZHX2 (Zhang et al., 2018).

A subset of these potential pVHL regulatory targets, including AKT, are proposed to interact with pVHL in a hydroxylproline-dependent manner following PHD-mediated hydroxylation. Notably, a systemic attempt to detect PHD-mediated hydroxylation of 24 non-HIFα substrates failed to reproduce and confirm previously published findings (Cockman et al., 2019). Further, a list of potential pVHL substrates, including fibronectin, collagen, tubulin, HuR, and p14/ARF, have been identified as pVHL interactors in high throughput studies with additional low-throughput supporting evidence in the BioGRID database (Oughtred et al., 2021). Each of these potential interactors, however, have only been identified in a single high-throughput experiment and all but HuR have been identified by the same high-throughput study (Lai et al., 2011; Oughtred et al., 2021). In contrast, the HIFα substrates of pVHL have been identified by numerous high-throughput and low throughput studies (143 identify HIF1α and 19 identify HIF2α in the BioGRID database) demonstrating a disparity in the confidence of the interactions (Oughtred et al., 2021). Thus, strong evidence of non-HIFα related bona fide biological functions of pVHL remains lacking.

Evidence for a HIF-centric model of VHL disease

Clinical evidence

Since the association of pVHL mutations with VHL disease, clinicians noted that largely unique groups of pVHL mutations were associated with the different types of VHL disease. It has been generally accepted that mutations that more markedly impact the ability of pVHL to degrade HIFα result in more ‘severe’ VHL disease phenotypes. Patients with large deletion and frameshift mutations generally develop Type 1 VHL disease, while patients with missense mutations develop Type 2 disease (Chen et al., 1995; Stolle et al., 1998; Maher et al., 1996). This concept can be further extrapolated to explain the heterogeneity of phenotypes within Type 2 VHL disease. Type 2c pVHL mutants, for example, cause exclusively pheochromocytoma and have been shown to degrade HIFα nearly as well as wild-type pVHL (Hoffman et al., 2001). Further, some pVHL mutations are associated with incomplete phenotypic penetrance, which has even been observed among members of the same VHL disease family. Thus, we propose that the various clinical phenotypes associated with VHL disease require different ‘doses’ of HIF. From polycythemia to pheochromocytoma to hemangioma/hemangioblastoma to RCC, a greater dose of HIF is required for disease onset. Inter-family heterogeneity among VHL disease patients reflects a differential loss of pVHL function — a mutation that completely abrogates the ability of pVHL to negatively regulate HIF leads to a greater HIF dose and more severe phenotype than mutations that only mildly impair pVHL function. Lastly, observed intra-family heterogeneity supports the idea that different phenotypes associated with VHL disease exist on a gradient of increasing HIF dose. Some individuals in a family, due to environmental, metabolic, and/or genetic factors, experience greater stabilization of HIF than other relatives with the same mutation, which leads to the development of phenotypes otherwise associated with greater loss of pVHL function (Figure 2).

Figure 2

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pVHL Y98 and Y112 are recognized as residues of interest as different missense mutations at these sites can elicit drastically different phenotypes. Both the Y98H and Y112H VHL mutations are classically associated with VHL Type 2a disease with a high penetrance of pheochromocytoma, but while the Y112H mutation appears to result in hemangioma/hemangioblastoma in only 20% of cases, the Y98H mutation displays a greater penetrance at ~50% (Brauch et al., 1995; Chen et al., 1996). This observation is also consistent with the fact that patients with the Y98H pVHL mutation are diagnosed earlier (mean of 19.7 years-old) than patients with the Y112H pVHL mutation (28.8 years-old) (Nielsen et al., 2011a). The fact that hemangioma/ hemangioblastoma penetrance lags behind pheochromocytoma penetrance in VHL disease patients with the Y112H mutation points to the idea of a gradient, where only a subset of these Type 2a patients develop the cardinal feature of vascular hemangioma/hemangioblastoma tumors.

In addition, a small number of patients with Type 2a pVHL mutants also develop RCC. Indeed, Type 2a VHL disease is classically defined as a ‘low’ chance of RCC rather than ‘no’ chance. A study of 16 families harboring the Y98H mutation found that some affected individuals exhibited symptoms consistent with Type 1 or 2b VHL disease. Out of 116 affected family members, 73 developed pheochromocytoma while 4 developed RCC (Brauch et al., 1995). Two individuals developed RCC in addition to pheochromocytoma (Type 2b) and two solely developed RCC (Type 1). Similarly, ~3% of individuals with the Y112H mutations also develop RCC (Nielsen et al., 2011b). In comparison, in a family harboring Y112N, 7 individuals developed RCC and only one developed pheochromocytoma, suggesting Y112N presents more commonly as Type 1 VHL disease (Bradley et al., 1999).

While Type 2c VHL disease is associated with pheochromocytoma, Type 2c mutations can sometimes ‘spillover’ and also cause hemangioma/hemangioblastoma. One example is the classic Type 2c VHL mutant V84L, which is associated solely with pheochromocytoma in most patients but in some cases, vascular tumors, including the possibility of spinal hemangioblastoma, and renal cysts are observed (Abbott et al., 2006). Similarly, the Type 2c VHL mutant G93S was linked with pheochromocytoma across multiple generations in a family with VHL disease, but further diagnostic workup revealed two retinal angiomas in the index patient and bilateral renal cysts in the index patient’s father (Schreinemakers et al., 2007). While renal cysts can be found in a population not carrying pVHL mutations, it is important to note that this could be evidence of progression of Type 2c VHL disease as individuals age.

As mentioned above, Type 2c VHL disease has perplexed the field as Type 2c pVHL mutants appear to regulate HIFα in a manner similar to wild-type pVHL, which would suggest that pheochromocytoma is uncoupled from HIFα degradation (Hoffman et al., 2001; Clifford et al., 2001). For example, a patient with bilateral pheochromocytoma and no other VHL-related symptoms was found to harbor a Y175C VHL mutation. When compared to wild-type pVHL, Y175C pVHL was able to degrade HIF efficiently under normoxic conditions (Astapova et al., 2018). But while in vitro studies failed to associate pheochromocytoma pathogenesis with HIF stabilization in the context of VHL disease, clinically observed EPAS1 (encodes HIF2α) and EGLN1 (encodes PHD2) mutations that result in HIF2α stabilization are now known to cause disease phenotypes that partially overlap with the VHL disease spectrum. Of particular interest, pheochromocytoma carcinogenesis is clinically associated with PHD2 loss-of-function mutations and HIF2α gain-of-function mutations in addition to pVHL loss-of-function mutations (Gardie et al., 2014; Ladroue et al., 2008; Därr et al., 2016; Taieb et al., 2016; Tarade et al., 2018). Therefore, it is possible that previous experiments suggesting the near wild-type activity of Type 2 c pVHL mutants lacked the sensitivity to assess differences in HIFα stabilization relative to wild-type pVHL that are biologically relevant. It is also possible that there is a more complex interplay between the relative stabilization of the different HIFα paralogs, which may be differentially affected by certain pVHL mutations.

HIF2-driven disease is particularly interesting because like VHL disease, it also presents as a gradient with escalating phenotypes comparable to Type 3, Type 2c, and even Type 2a VHL disease. Patients with mutations in EPAS1, the gene encoding HIF2α, have been reported to develop polycythemia and neuroendocrine tumors in dozens of patients (Därr et al., 2016; Taieb et al., 2016; Tarade et al., 2018). HIF2-driven disease can be segregated into two broad classes: Class 1 characterized by the presence of pheochromocytoma and/or paraganglioma (PPGL) with or without polycythemia, and Class 2 in which patients present solely with polycythemia (Tarade et al., 2018). Class 1 is further divided into three sub-classes where Class 1a presents with PPGL, somatostatinoma, and polycythemia, Class 1b presents with PPGL and polycythemia, and Class 1c presents with PPGL exclusively (Table 2). More rarely, patients with gain-of-function HIF2α mutations also present with hemangiomas and hemangioblastoma. While there is only a single case of hemangioblastoma linked to a HIF2α gain-of-function mutation, a unique and uncharacterized double F374Y and Q561K missense mutation, (Taieb et al., 2016) the clinical literature includes three reports of patients with HIF2-driven disease developing hemangiomas of the retina, liver, and cranial vault (Pacak et al., 2013; Dmitriev et al., 2020; Buffet et al., 2014). All three of these patients also developed polycythemia and pheochromocytoma/paraganglioma and were determined to have a HIF2α gain-of-function mutation otherwise associated with a complete penetrance of PPGL. While there is less clinical evidence of HIF2α driving hemangioma, relative to PPGL, liver hemangiomas associated with loss-of-pVHL mouse models can be rescued by co-deletion of HIF2α or HIFβ, which provides further evidence for the gatekeeping role of HIF2α in hemangioma and hemangioblastoma (Rankin et al., 2008; Rankin et al., 2005). Much like Type 2c VHL disease, Class 1a/b HIF2-driven disease can sometimes ‘spillover’ and trigger the formation of vascular hemangioma tumors. The remarkable fact that HIF2α gain-of-function mutations can phenocopy Type 2a VHL disease provides strong evidence for the role of HIF2α in Type 2c VHL disease. Not only do some canonical Type 2c VHL mutations also cause hemangiomas, a phenotype strongly linked with HIF2α signaling in Type 2a VHL disease, some VHL disease patients concurrently develop polycythemia, pheochromocytoma, and somatostatinoma, which matches the phenotypic profile of Class 1a HIF2-driven disease (Karasawa et al., 2001).

Table 2

HIF2-driven disease
	Class 1A	Class 1B	Class 1C	Class 2
PPGL	+	+	+	-
Somatostatinoma	+	-	-	-
Polycythemia	+	+	-	+

PHD2 mutations have been widely found to cause polycythemia. More rarely, PHD2 mutations, like PHD2 H374R and PHD2 A228S, trigger development of pheochromocytoma and/or paraganglioma (PPGL) in addition to polycythemia (Gardie et al., 2014; Ladroue et al., 2008; Yang et al., 2015). The patient harboring the H374R mutant originally presented with erythrocytosis, but a tumor matching the characteristics of a paraganglioma was later diagnosis at 43 years old (Ladroue et al., 2008) This individual displayed loss of the remaining wild-type EGLN1 allele. This observed loss of heterozygosity suggests that PHD2 plays a tumor suppressor role in chromaffin cells and the closely related paraganglia cells that are transformed in paraganglioma. Other reports of PHD2 mutation in polycythemia note that patients inherit a single mutated allele (Percy et al., 2006; Percy et al., 2007; Barradas et al., 2018). This could imply that haploinsufficiency of wild-type PHD2 might be enough to induce symptoms. Indeed, deletion of a single PHD2 allele or knock-in of a single mutant PHD2 allele in mice successfully recapitulates polycythemia, which was also found to be dependent on HIF2α (Arsenault et al., 2013). These cases also suggest mutations of EGLN1 may have a limited phenotypic range compared to VHL and HIF2-driven disease. The loss of PHD2 function may be compensated for by the other PHD paralogs, PHD1 and PHD3, preventing most instances of tumor formation but not all. Indeed, there has been one documented case of a disease-causing PHD1 mutation. This mutant, S61R, induced erythrocytosis development by age 6 and recurrent PPGL at age 14 (Yang et al., 2015).

There have also been documented cases of pVHL mutant-induced polycythemia (Type 3 VHL disease). R200W and H191D have both been identified as autosomal-recessive pVHL mutations that cause polycythemia (Pastore et al., 2003; Ang et al., 2002). And similarly to the role of HIF2α in liver hemangioma pathogenesis in loss-of-pVHL mouse models, inhibition of HIF2α rescues polycythemia in mouse models of polycythemia driven by the R200W mutation (Ghosh et al., 2021; Hickey et al., 2007; Ghosh et al., 2018).

While pVHL induced polycythemia is generally inherited in an autosomal-recessive manner, a study investigating eight children with polycythemia revealed one case in which a family harbored a heterozygous VHL mutant inducing a phenotype. Two siblings in the family were found to be heterozygous for D126Y and had increased levels of hematocrit and erythropoietin. One of the siblings had a history of tumors, developing a pulmonary angioma at age 10 and a renal subcapsular hemangioma at age 15. This would indicate that pVHL D126Y straddles the line between Type 3 and Type 2a disease. All the patients in this study were young (10–19 years old; Pastore et al., 2003); therefore, it remains unclear whether these patients will develop tumors later in life.

Just like VHL disease, HIF2α and PHD2 mutations can present a wide range of phenotypes where mutations that most stabilize HIF2α cause the worst phenotypes (more on this later). Thus, mutations in these three separate components of the HIFα-degradation pathway — substrate (HIF2α), hydroxylase (PHD2), and E3 ubiquitin ligase (pVHL) — all present with similar phenotypes. The common factor in the disruption of these three components of the pathway is the ultimate stabilization of HIFα, in particular HIF2α, and the correlation between the severity of disease and the degree of disruption to the HIFα degradation pathway naturally suggest that the causative factor is HIFα (Figure 2).

Fully elucidating molecular mechanism underlying VHL disease remains difficult given a dearth of relevant culture and animal models. VHL-null kidney cancer cell lines led to the discovery of the role of pVHL and prolyl hydroxylases in negatively regulating HIF, but overexpression of mutant pVHL, PHD2, or HIF2α remains a blunt tool that is not well-suited for differentiating different disease classes. Without a cell culture system relevant to the RCC, hemangioma or PPGL carcinogenesis process, the principal readout available is overall stabilization of HIF2α, a decidedly qualitative result. Thus, the study of pseudohypoxic disease, which benefits greatly from rich clinical data, requires a model for the one-to-one comparison of pVHL, HIF2α, and PHD2 mutants. If our HIF-centric model of pseudohypoxic disease holds then we would expect that Type 2c pVHL mutants would result in similar HIF2α stabilization as Class 1 HIF2α mutants or cancer-causing PHD2 mutants; Type 2a pVHL mutants would result in greater stabilization of HIF2α than either Type 2c pVHL mutants or Class HIF2α mutants; and Type 2b pVHL mutants would result in even greater stabilization of HIF2α.

Any model developed to assess the HIF-centric model of VHL disease, where increasing dysregulation of HIF corresponds to a wider range of phenotypes, will need to be able to assess overall HIF stabilization in a system that includes all components of the PHD-pVHL-HIF axis. Further, these components will need to reflect physiologically relevant concentrations. Lastly, quantitative readouts directly related to the stabilization of HIF2α and/or HIF1α would be required.

Although possible to recapitulate the PHD-pVHL-HIF axis in living systems, the ability to introduce disease-causing mutations without over-expressing one component is limited. CRISPR-mediated gene editing of endogenous VHL, EGLN1, or EPAS1 loci remains one possibility to directly compare the impact of disease-causing mutations on the regulation of cellular HIF pools. By comparing this cellular data with known clinical phenotypes, the HIF-centric model could be directly addressed.

Further, there is some limited success in recapitulating pseudohypoxic disease phenotypes in mice (Rankin et al., 2005; Hickey et al., 2007; Wang et al., 2019; Tan et al., 2013). Generation of transgenic mice with representative VHL, EGLN1, and EPAS1 mutants thus represents another avenue by which the HIF-centric model can be tested. So far, polycythemia has been recapitulated in transgenic mice with either VHL loss or EPAS1 gain-of-function mutation. Importantly, a gradient in EPO levels could be discerned between heterozygous and homozygous HIF2α gain-of-function mutation, suggesting this is a sensitive and quantitative readout (Tan et al., 2013). Unfortunately, it’s been difficult to generate a mouse model of pseudohypoxic pheochromocytoma or paraganglioma (Lussey-Lepoutre et al., 2018). One exception is the work of the Bishop group where the inactivation of PHD2 in the Type 1 cells of carotid body resulted in the formation of paraganglioma (Fielding et al., 2018).

Another possible model for testing the HIF-centric hypothesis is the in vitro reconstitution of the entire pVHL-PHD-HIF axis. Purification of PHD2, pVHL-E3 ubiquitin ligase complex, and fluorescein-labeled HIF2α would allow for the real-time monitoring of HIF2α ubiquitylation and degradation. By substituting wild-type components with disease-associated mutations, the level of HIF2α stabilization could be precisely assessed and compared to known clinical phenotypes.

Lastly, the development and clinical evaluation of a specific HIF2α inhibitor, Belzutifan, represents another opportunity to assess the necessity of HIF2α activity for the various clinical manifestations associated with VHL disease (Cho et al., 2016; Chen et al., 2016). Recently, Belzutifan received approval in the US for treatment of RCC, hemangioblastoma, and pancreatic neuroendrocrine tumors (pNET) associated with VHL disease following a successful phase 3 clinical trial (Fallah et al., 2022). A small number of pheochromocytoma tumors in that clinical trial meant that the critical requirement of HIF2α signaling for VHL disease-associated pheochromocytoma could not be assessed, but a single-patient clinical trial of a patient with Pacak-Zhuang syndrome (another name for Class 1a/b HIF2-driven disease) revealed that Belzutifan treatment can result in the shrinkage of paraganglioma tumors and the resolution of polycythemia (Kamihara et al., 2021). Expanded studies evaluating the efficacy of Belzutifan in PPGL tumors associated with VHL disease and HIF2-driven disease will allow for the exploration of the necessity of HIF2α for PPGL in different genetic contexts.

1. 1. Abbott MA
   2. Nathanson KL
   3. Nightingale S
   4. Maher ER
   5. Greenstein RM

   (2006) The von hippel-lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma

   American Journal of Medical Genetics. Part A 140:685–690.

   https://doi.org/10.1002/ajmg.a.31116

   • PubMed
   • Google Scholar
2. 1. Ang SO
   2. Chen H
   3. Hirota K
   4. Gordeuk VR
   5. Jelinek J
   6. Guan Y
   7. Liu E
   8. Sergueeva AI
   9. Miasnikova GY
   10. Mole D
   11. Maxwell PH
   12. Stockton DW
   13. Semenza GL
   14. Prchal JT

   (2002) Disruption of oxygen homeostasis underlies congenital chuvash polycythemia

   Nature Genetics 32:614–621.

   https://doi.org/10.1038/ng1019

   • PubMed
   • Google Scholar
3. 1. Anisimov VN

   (2003) The relationship between aging and carcinogenesis: a critical appraisal

   Critical Reviews in Oncology/Hematology 45:277–304.

   https://doi.org/10.1016/s1040-8428(02)00121-x

   • PubMed
   • Google Scholar
4. 1. Appelhoff RJ
   2. Tian YM
   3. Raval RR
   4. Turley H
   5. Harris AL
   6. Pugh CW
   7. Ratcliffe PJ
   8. Gleadle JM

   (2004) Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor

   The Journal of Biological Chemistry 279:38458–38465.

   https://doi.org/10.1074/jbc.M406026200

   • PubMed
   • Google Scholar
5. 1. Arias-Stella J
   2. Valcarcel J

   (1976) Chief cell hyperplasia in the human carotid body at high altitudes; physiologic and pathologic significance

   Human Pathology 7:361–373.

   https://doi.org/10.1016/s0046-8177(76)80052-4

   • PubMed
   • Google Scholar
6. 1. Arsenault PR
   2. Pei F
   3. Lee R
   4. Kerestes H
   5. Percy MJ
   6. Keith B
   7. Simon MC
   8. Lappin TRJ
   9. Khurana TS
   10. Lee FS

   (2013) A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes A haploinsufficiency mechanism

   The Journal of Biological Chemistry 288:33571–33584.

   https://doi.org/10.1074/jbc.M113.482364

   • PubMed
   • Google Scholar
7. 1. Astapova O
   2. Biswas A
   3. DiMauro A
   4. Moalem J
   5. Hammes SR

   (2018) Bilateral pheochromocytomas in a patient with Y175C von hippel-lindau mutation

   Case Reports in Endocrinology 2018:8967159.

   https://doi.org/10.1155/2018/8967159

   • PubMed
   • Google Scholar
8. 1. Astrom K
   2. Cohen JE
   3. Willett-Brozick JE
   4. Aston CE
   5. Baysal BE

   (2003) Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect

   Human Genetics 113:228–237.

   https://doi.org/10.1007/s00439-003-0969-6

   • PubMed
   • Google Scholar
9. 1. Astuti D
   2. Ricketts CJ
   3. Chowdhury R
   4. McDonough MA
   5. Gentle D
   6. Kirby G
   7. Schlisio S
   8. Kenchappa RS
   9. Carter BD
   10. Kaelin WG
   11. Ratcliffe PJ
   12. Schofield CJ
   13. Latif F
   14. Maher ER

   (2011) Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility

   Endocrine-Related Cancer 18:73–83.

   https://doi.org/10.1677/ERC-10-0113

   • PubMed
   • Google Scholar
10. 1. Barradas J
    2. Rodrigues CD
    3. Ferreira G
    4. Rocha P
    5. Constanço C
    6. Andrade MR
    7. Bento C
    8. Silva HM

    (2018) Congenital erythrocytosis - discover of a new mutation in the EGLN1 gene

    Clinical Case Reports 6:1109–1111.

    https://doi.org/10.1002/ccr3.1499

    • PubMed
    • Google Scholar
11. 1. Bradley JF
    2. Collins DL
    3. Schimke RN
    4. Parrott HN
    5. Rothberg PG

    (1999) Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene

    American Journal of Medical Genetics 87:163–167.

    https://doi.org/10.1002/(sici)1096-8628(19991119)87:2<163::aid-ajmg7>3.0.co;2-a

    • PubMed
    • Google Scholar
12. 1. Brauch H
    2. Kishida T
    3. Glavac D
    4. Chen F
    5. Pausch F
    6. Höfler H
    7. Latif F
    8. Lerman MI
    9. Zbar B
    10. Neumann HP

    (1995) Von hippel-lindau (VHL) disease with pheochromocytoma in the black forest region of germany: evidence for a founder effect

    Human Genetics 95:551–556.

    https://doi.org/10.1007/BF00223868

    • PubMed
    • Google Scholar
13. 1. Bruick RK
    2. McKnight SL

    (2001) A conserved family of prolyl-4-hydroxylases that modify HIF

    Science 294:1337–1340.

    https://doi.org/10.1126/science.1066373

    • PubMed
    • Google Scholar
14. 1. Buffet A
    2. Smati S
    3. Mansuy L
    4. Ménara M
    5. Lebras M
    6. Heymann MF
    7. Simian C
    8. Favier J
    9. Murat A
    10. Cariou B
    11. Gimenez-Roqueplo AP

    (2014) Mosaicism in HIF2A-related polycythemia-paraganglioma syndrome

    The Journal of Clinical Endocrinology and Metabolism 99:E369–E373.

    https://doi.org/10.1210/jc.2013-2600

    • PubMed
    • Google Scholar
15. 1. Cardote TAF
    2. Gadd MS
    3. Ciulli A

    (2017) Crystal structure of the cul2-rbx1-elobc-VHL ubiquitin ligase complex

    Structure 25:901–911.

    https://doi.org/10.1016/j.str.2017.04.009

    • PubMed
    • Google Scholar
16. 1. Chen F
    2. Kishida T
    3. Yao M
    4. Hustad T
    5. Glavac D
    6. Dean M
    7. Gnarra JR
    8. Orcutt ML
    9. Duh FM
    10. Glenn G

    (1995) Germline mutations in the von hippel-lindau disease tumor suppressor gene: correlations with phenotype

    Human Mutation 5:66–75.

    https://doi.org/10.1002/humu.1380050109

    • PubMed
    • Google Scholar
17. 1. Chen F
    2. Slife L
    3. Kishida T
    4. Mulvihill J
    5. Tisherman SE
    6. Zbar B

    (1996) Genotype-phenotype correlation in von hippel-lindau disease: identification of a mutation associated with VHL type 2A

    Journal of Medical Genetics 33:716–717.

    https://doi.org/10.1136/jmg.33.8.716

    • PubMed
    • Google Scholar
18. 1. Chen W
    2. Hill H
    3. Christie A
    4. Kim MS
    5. Holloman E
    6. Pavia-Jimenez A
    7. Homayoun F
    8. Ma Y
    9. Patel N
    10. Yell P
    11. Hao G
    12. Yousuf Q
    13. Joyce A
    14. Pedrosa I
    15. Geiger H
    16. Zhang H
    17. Chang J
    18. Gardner KH
    19. Bruick RK
    20. Reeves C
    21. Hwang TH
    22. Courtney K
    23. Frenkel E
    24. Sun X
    25. Zojwalla N
    26. Wong T
    27. Rizzi JP
    28. Wallace EM
    29. Josey JA
    30. Xie Y
    31. Xie XJ
    32. Kapur P
    33. McKay RM
    34. Brugarolas J

    (2016) Targeting renal cell carcinoma with a HIF-2 antagonist

    Nature 539:112–117.

    https://doi.org/10.1038/nature19796

    • PubMed
    • Google Scholar
19. 1. Cho H
    2. Du X
    3. Rizzi JP
    4. Liberzon E
    5. Chakraborty AA
    6. Gao W
    7. Carvo I
    8. Signoretti S
    9. Bruick RK
    10. Josey JA
    11. Wallace EM
    12. Kaelin WG

    (2016) On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

    Nature 539:107–111.

    https://doi.org/10.1038/nature19795

    • PubMed
    • Google Scholar
20. 1. Clifford SC
    2. Cockman ME
    3. Smallwood AC
    4. Mole DR
    5. Woodward ER
    6. Maxwell PH
    7. Ratcliffe PJ
    8. Maher ER

    (2001) Contrasting effects on HIF-1alpha regulation by disease-causing pvhl mutations correlate with patterns of tumourigenesis in von hippel-lindau disease

    Human Molecular Genetics 10:1029–1038.

    https://doi.org/10.1093/hmg/10.10.1029

    • PubMed
    • Google Scholar
21. 1. Cockman ME
    2. Lippl K
    3. Tian YM
    4. Pegg HB
    5. Figg WD
    6. Abboud MI
    7. Heilig R
    8. Fischer R
    9. Myllyharju J
    10. Schofield CJ
    11. Ratcliffe PJ

    (2019) Lack of activity of recombinant HIF prolyl hydroxylases (phds) on reported non-HIF substrates

    eLife 8:e46490.

    https://doi.org/10.7554/eLife.46490

    • PubMed
    • Google Scholar
22. 1. Crossey PA
    2. Eng C
    3. Ginalska-Malinowska M
    4. Lennard TW
    5. Wheeler DC
    6. Ponder BA
    7. Maher ER

    (1995) Molecular genetic diagnosis of von hippel-lindau disease in familial phaeochromocytoma

    Journal of Medical Genetics 32:885–886.

    https://doi.org/10.1136/jmg.32.11.885

    • PubMed
    • Google Scholar
23. 1. Cummins EP
    2. Berra E
    3. Comerford KM
    4. Ginouves A
    5. Fitzgerald KT
    6. Seeballuck F
    7. Godson C
    8. Nielsen JE
    9. Moynagh P
    10. Pouyssegur J
    11. Taylor CT

    (2006) Prolyl hydroxylase-1 negatively regulates ikappab kinase-beta, giving insight into hypoxia-induced nfkappab activity

    PNAS 103:18154–18159.

    https://doi.org/10.1073/pnas.0602235103

    • PubMed
    • Google Scholar
24. 1. Danilin S
    2. Sourbier C
    3. Thomas L
    4. Rothhut S
    5. Lindner V
    6. Helwig JJ
    7. Jacqmin D
    8. Lang H
    9. Massfelder T

    (2009) 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 30:387–396.

    https://doi.org/10.1093/carcin/bgn275

    • PubMed
    • Google Scholar
25. 1. Därr R
    2. Nambuba J
    3. Del Rivero J
    4. Janssen I
    5. Merino M
    6. Todorovic M
    7. Balint B
    8. Jochmanova I
    9. Prchal JT
    10. Lechan RM
    11. Tischler AS
    12. Popovic V
    13. Miljic D
    14. Adams KT
    15. Prall FR
    16. Ling A
    17. Golomb MR
    18. Ferguson M
    19. Nilubol N
    20. Chen CC
    21. Chew E
    22. Taïeb D
    23. Stratakis CA
    24. Fojo T
    25. Yang C
    26. Kebebew E
    27. Zhuang Z
    28. Pacak K

    (2016) Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome

    Endocrine-Related Cancer 23:899–908.

    https://doi.org/10.1530/ERC-16-0231

    • PubMed
    • Google Scholar
26. 1. Davison C
    2. Brok S
    3. Cyke CG

    (1936)

    Retinal and central nervous hemangioblastomatosis with visceral changes (von hippel-lindau’s disease)

    Bull Neurol Inst New York 5:72–93.

    • Google Scholar
27. 1. Dmitriev PM
    2. Wang H
    3. Rosenblum JS
    4. Prodanov T
    5. Cui J
    6. Pappo AS
    7. Gilbert MR
    8. Lutty GA
    9. Chan CC
    10. Chew EY
    11. Pacak K
    12. Zhuang Z

    (2020) Vascular changes in the retina and choroid of patients with EPAS1 gain-of-function mutation syndrome

    JAMA Ophthalmology 138:148–155.

    https://doi.org/10.1001/jamaophthalmol.2019.5244

    • PubMed
    • Google Scholar
28. 1. Dwight T
    2. Kim E
    3. Bastard K
    4. Benn DE
    5. Eisenhofer G
    6. Richter S
    7. Mannelli M
    8. Rapizzi E
    9. Prejbisz A
    10. Pęczkowska M
    11. Pacak K
    12. Clifton-Bligh R

    (2021) Functional significance of germline EPAS1 variants

    Endocrine-Related Cancer 28:97–109.

    https://doi.org/10.1530/ERC-20-0280

    • PubMed
    • Google Scholar
29. 1. Epstein AC
    2. Gleadle JM
    3. McNeill LA
    4. Hewitson KS
    5. O’Rourke J
    6. Mole DR
    7. Mukherji M
    8. Metzen E
    9. Wilson MI
    10. Dhanda A
    11. Tian YM
    12. Masson N
    13. Hamilton DL
    14. Jaakkola P
    15. Barstead R
    16. Hodgkin J
    17. Maxwell PH
    18. Pugh CW
    19. Schofield CJ
    20. Ratcliffe PJ

    (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation

    Cell 107:43–54.

    https://doi.org/10.1016/s0092-8674(01)00507-4

    • PubMed
    • Google Scholar
30. 1. Esteban MA
    2. Harten SK
    3. Tran MG
    4. Maxwell PH

    (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 17:1801–1806.

    https://doi.org/10.1681/ASN.2006020181

    • PubMed
    • Google Scholar
31. 1. Fallah J
    2. Brave MH
    3. Weinstock C
    4. Mehta GU
    5. Bradford D
    6. Gittleman H
    7. Bloomquist EW
    8. Charlab R
    9. Hamed SS
    10. Miller CP
    11. Dorff SE
    12. Chambers WA
    13. Mixter BD
    14. Dinin J
    15. Pierce WF
    16. Ricks TK
    17. Tang S
    18. Donoghue M
    19. Pazdur R
    20. Amiri-Kordestani L
    21. Ibrahim A
    22. Beaver JA

    (2022) FDA approval summary: belzutifan for von hippel-lindau disease associated tumors

    Clinical Cancer Research 1:clincanres.1054.2022-4-4 11:16:38.037.

    https://doi.org/10.1158/1078-0432.CCR-22-1054

    • PubMed
    • Google Scholar
32. 1. Fielding JW
    2. Hodson EJ
    3. Cheng X
    4. Ferguson DJP
    5. Eckardt L
    6. Adam J
    7. Lip P
    8. Maton-Howarth M
    9. Ratnayaka I
    10. Pugh CW
    11. Buckler KJ
    12. Ratcliffe PJ
    13. Bishop T

    (2018) PHD2 inactivation in type I cells drives HIF-2α-dependent multilineage hyperplasia and the formation of paraganglioma-like carotid bodies

    The Journal of Physiology 596:4393–4412.

    https://doi.org/10.1113/JP275996

    • PubMed
    • Google Scholar
33. 1. Forman JR
    2. Worth CL
    3. Bickerton GRJ
    4. Eisen TG
    5. Blundell TL

    (2009) Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von hippel-lindau disease and suggests molecular mechanisms of tumorigenesis

    Proteins 77:84–96.

    https://doi.org/10.1002/prot.22419

    • PubMed
    • Google Scholar
34. 1. Fu L
    2. Wang G
    3. Shevchuk MM
    4. Nanus DM
    5. Gudas LJ

    (2011) Generation of a mouse model of von hippel-lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1α

    Cancer Research 71:6848–6856.

    https://doi.org/10.1158/0008-5472.CAN-11-1745

    • PubMed
    • Google Scholar
35. 1. Fu L
    2. Wang G
    3. Shevchuk MM
    4. Nanus DM
    5. Gudas LJ

    (2013) Activation of HIF2α in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis

    Cancer Research 73:2916–2925.

    https://doi.org/10.1158/0008-5472.CAN-12-3983

    • PubMed
    • Google Scholar
36. 1. Fu L
    2. Minton DR
    3. Zhang T
    4. Nanus DM
    5. Gudas LJ

    (2015) Genome-wide profiling of TRACK kidneys shows similarity to the human ccrcc transcriptome

    Molecular Cancer Research 13:870–878.

    https://doi.org/10.1158/1541-7786.MCR-14-0423

    • PubMed
    • Google Scholar
37. 1. Gao W
    2. Li W
    3. Xiao T
    4. Liu XS
    5. Kaelin WG

    (2017) Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL ^−/− clear cell renal carcinoma

    PNAS 114:1027–1032.

    https://doi.org/10.1073/pnas.1619726114

    • Google Scholar
38. 1. Gardie B
    2. Percy MJ
    3. Hoogewijs D
    4. Chowdhury R
    5. Bento C
    6. Arsenault PR
    7. Richard S
    8. Almeida H
    9. Ewing J
    10. Lambert F
    11. McMullin MF
    12. Schofield CJ
    13. Lee FS

    (2014) The role of PHD2 mutations in the pathogenesis of erythrocytosis

    Hypoxia 2:71–90.

    https://doi.org/10.2147/HP.S54455

    • PubMed
    • Google Scholar
39. 1. Ghosh MC
    2. Zhang DL
    3. Ollivierre H
    4. Eckhaus MA
    5. Rouault TA

    (2018) Translational repression of HIF2α expression in mice with chuvash polycythemia reverses polycythemia

    The Journal of Clinical Investigation 128:1317–1325.

    https://doi.org/10.1172/JCI97684

    • PubMed
    • Google Scholar
40. 1. Ghosh MC
    2. Zhang D-L
    3. Ollivierre WH
    4. Noguchi A
    5. Springer DA
    6. Linehan WM
    7. Rouault TA

    (2021) Therapeutic inhibition of HIF-2α reverses polycythemia and pulmonary hypertension in murine models of human diseases

    Blood 137:2509–2519.

    https://doi.org/10.1182/blood.2020009138

    • PubMed
    • Google Scholar
41. 1. Grosfeld A
    2. Stolze IP
    3. Cockman ME
    4. Pugh CW
    5. Edelmann M
    6. Kessler B
    7. Bullock AN
    8. Ratcliffe PJ
    9. Masson N

    (2007) Interaction of hydroxylated collagen IV with the von hippel-lindau tumor suppressor

    The Journal of Biological Chemistry 282:13264–13269.

    https://doi.org/10.1074/jbc.M611648200

    • PubMed
    • Google Scholar
42. 1. Guo J
    2. Chakraborty AA
    3. Liu P
    4. Gan W
    5. Zheng X
    6. Inuzuka H
    7. Wang B
    8. Zhang J
    9. Zhang L
    10. Yuan M
    11. Novak J
    12. Cheng JQ
    13. Toker A
    14. Signoretti S
    15. Zhang Q
    16. Asara JM
    17. Kaelin WG
    18. Wei W

    (2016) PVHL suppresses kinase activity of akt in a proline-hydroxylation-dependent manner

    Science 353:929–932.

    https://doi.org/10.1126/science.aad5755

    • PubMed
    • Google Scholar
43. 1. Hacker KE
    2. Lee CM
    3. Rathmell WK

    (2008) VHL type 2B mutations retain VBC complex form and function

    PLOS ONE 3:e3801.

    https://doi.org/10.1371/journal.pone.0003801

    • PubMed
    • Google Scholar
44. 1. Heath D
    2. Edwards C
    3. Harris P

    (1970) Post-mortem size and structure of the human carotid body: its relation to pulmonary disease and cardiac hypertrophy

    Thorax 25:129–140.

    https://doi.org/10.1136/thx.25.2.129

    • Google Scholar
45. 1. Hergovich A
    2. Lisztwan J
    3. Barry R
    4. Ballschmieter P
    5. Krek W

    (2003) Regulation of microtubule stability by the von hippel-lindau tumour suppressor protein pvhl

    Nature Cell Biology 5:64–70.

    https://doi.org/10.1038/ncb899

    • PubMed
    • Google Scholar
46. 1. Hergovich A
    2. Lisztwan J
    3. Thoma CR
    4. Wirbelauer C
    5. Barry RE
    6. Krek W

    (2006) Priming-dependent phosphorylation and regulation of the tumor suppressor pvhl by glycogen synthase kinase 3

    Molecular and Cellular Biology 26:5784–5796.

    https://doi.org/10.1128/MCB.00232-06

    • PubMed
    • Google Scholar
47. 1. Hickey MM
    2. Lam JC
    3. Bezman NA
    4. Rathmell WK
    5. Simon MC

    (2007) Von hippel-lindau mutation in mice recapitulates chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis

    The Journal of Clinical Investigation 117:3879–3889.

    https://doi.org/10.1172/JCI32614

    • PubMed
    • Google Scholar
48. 1. Hippel E

    (1904) Über eine sehr seltene erkrankung der netzhaut

    Albrecht von Græfe’s Archiv Für Ophthalmologie 59:83–106.

    https://doi.org/10.1007/BF01994821

    • Google Scholar
49. 1. Hoefflin R
    2. Harlander S
    3. Schäfer S
    4. Metzger P
    5. Kuo F
    6. Schönenberger D
    7. Adlesic M
    8. Peighambari A
    9. Seidel P
    10. Chen C-Y
    11. Consenza-Contreras M
    12. Jud A
    13. Lahrmann B
    14. Grabe N
    15. Heide D
    16. Uhl FM
    17. Chan TA
    18. Duyster J
    19. Zeiser R
    20. Schell C
    21. Heikenwalder M
    22. Schilling O
    23. Hakimi AA
    24. Boerries M
    25. Frew IJ

    (2020) HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice

    Nature Communications 11:4111.

    https://doi.org/10.1038/s41467-020-17873-3

    • PubMed
    • Google Scholar
50. 1. Hoffman MA
    2. Ohh M
    3. Yang H
    4. Klco JM
    5. Ivan M
    6. Kaelin WG Jr

    (2001) Von hippel-lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF

    Human Molecular Genetics 10:1019–1027.

    https://doi.org/10.1093/hmg/10.10.1019

    • PubMed
    • Google Scholar
51. 1. Ivan M
    2. Kondo K
    3. Yang H
    4. Kim W
    5. Valiando J
    6. Ohh M
    7. Salic A
    8. Asara JM
    9. Lane WS
    10. Kaelin WG Jr

    (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing

    Science 292:464–468.

    https://doi.org/10.1126/science.1059817

    • PubMed
    • Google Scholar
52. 1. Jaakkola P
    2. Mole DR
    3. Tian YM
    4. Wilson MI
    5. Gielbert J
    6. Gaskell SJ
    7. von Kriegsheim A
    8. Hebestreit HF
    9. Mukherji M
    10. Schofield CJ
    11. Maxwell PH
    12. Pugh CW
    13. Ratcliffe PJ

    (2001) Targeting of HIF-alpha to the von hippel-lindau ubiquitylation complex by O2-regulated prolyl hydroxylation

    Science 292:468–472.

    https://doi.org/10.1126/science.1059796

    • PubMed
    • Google Scholar
53. 1. Jiang BH
    2. Rue E
    3. Wang GL
    4. Roe R
    5. Semenza GLD

    (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1

    The Journal of Biological Chemistry 271:17771–17778.

    https://doi.org/10.1074/jbc.271.30.17771

    • PubMed
    • Google Scholar
54. 1. Kaelin WG
    2. Ratcliffe PJ

    (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway

    Molecular Cell 30:393–402.

    https://doi.org/10.1016/j.molcel.2008.04.009

    • PubMed
    • Google Scholar
55. 1. Kamihara J
    2. Hamilton KV
    3. Pollard JA
    4. Clinton CM
    5. Madden JA
    6. Lin J
    7. Imamovic A
    8. Wall CB
    9. Wassner AJ
    10. Weil BR
    11. Heeney MM
    12. Vargas SO
    13. Kaelin WG
    14. Janeway KA
    15. Perini RF
    16. Zojwalla NJ
    17. Voss SD
    18. DuBois SG

    (2021) Belzutifan, a potent HIF2α inhibitor, in the pacak-zhuang syndrome

    The New England Journal of Medicine 385:2059–2065.

    https://doi.org/10.1056/NEJMoa2110051

    • PubMed
    • Google Scholar
56. 1. Kamura T
    2. Koepp DM
    3. Conrad MN
    4. Skowyra D
    5. Moreland RJ
    6. Iliopoulos O
    7. Lane WS
    8. Kaelin WG
    9. Elledge SJ
    10. Conaway RC
    11. Harper JW
    12. Conaway JW

    (1999) Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase

    Science 284:657–661.

    https://doi.org/10.1126/science.284.5414.657

    • PubMed
    • Google Scholar
57. 1. Karasawa Y
    2. Sakaguchi M
    3. Minami S
    4. Kitano K
    5. Kawa S
    6. Aoki Y
    7. Itoh N
    8. Sakurai A
    9. Miyazaki M
    10. Watanabe T
    11. Akimoto M
    12. Arakura N
    13. Kiyosawa K

    (2001) Duodenal somatostatinoma and erythrocytosis in a patient with von hippel-lindau disease type 2A

    Internal Medicine 40:38–43.

    https://doi.org/10.2169/internalmedicine.40.38

    • Google Scholar
58. 1. Knauth K
    2. Bex C
    3. Jemth P
    4. Buchberger A

    (2006) Renal cell carcinoma risk in type 2 von hippel-lindau disease correlates with defects in pvhl stability and HIF-1alpha interactions

    Oncogene 25:370–377.

    https://doi.org/10.1038/sj.onc.1209062

    • PubMed
    • Google Scholar
59. 1. Knauth K
    2. Cartwright E
    3. Freund S
    4. Bycroft M
    5. Buchberger A

    (2009) VHL mutations linked to type 2C von hippel-lindau disease cause extensive structural perturbations in pvhl

    The Journal of Biological Chemistry 284:10514–10522.

    https://doi.org/10.1074/jbc.M809056200

    • PubMed
    • Google Scholar
60. 1. Kondo K
    2. Klco J
    3. Nakamura E
    4. Lechpammer M
    5. Kaelin WG

    (2002) Inhibition of HIF is necessary for tumor suppression by the von hippel-lindau protein

    Cancer Cell 1:237–246.

    https://doi.org/10.1016/s1535-6108(02)00043-0

    • PubMed
    • Google Scholar
61. 1. Kondo K
    2. Kim WY
    3. Lechpammer M
    4. Kaelin WG

    (2003) Inhibition of hif2alpha is sufficient to suppress pvhl-defective tumor growth

    PLOS Biology 1:E83.

    https://doi.org/10.1371/journal.pbio.0000083

    • PubMed
    • Google Scholar
62. 1. Kurban G
    2. Duplan E
    3. Ramlal N
    4. Hudon V
    5. Sado Y
    6. Ninomiya Y
    7. Pause A

    (1998a) Collagen matrix assembly is driven by the interaction of von hippel–lindau tumor suppressor protein with hydroxylated collagen IV alpha 2

    Oncogene 27:1004–1012.

    https://doi.org/10.1038/sj.onc.1210709

    • PubMed
    • Google Scholar
63. 1. Kurban G
    2. Hudon V
    3. Duplan E
    4. Ohh M
    5. Pause A

    (1998b) Characterization of a von hippel lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis

    Cancer Research 66:1313–1319.

    https://doi.org/10.1158/0008-5472.CAN-05-2560

    • PubMed
    • Google Scholar
64. 1. Lack EE

    (1977) Carotid body hypertrophy in patients with cystic fibrosis and cyanotic congenital heart disease

    Human Pathology 8:39–51.

    https://doi.org/10.1016/s0046-8177(77)80064-6

    • PubMed
    • Google Scholar
65. 1. Lack EE

    (1978)

    Hyperplasia of vagal and carotid body paraganglia in patients with chronic hypoxemia

    The American Journal of Pathology 91:497–516.

    • PubMed
    • Google Scholar
66. 1. Ladroue C
    2. Carcenac R
    3. Leporrier M
    4. Gad S
    5. Le Hello C
    6. Galateau-Salle F
    7. Feunteun J
    8. Pouysségur J
    9. Richard S
    10. Gardie B

    (2008) PHD2 mutation and congenital erythrocytosis with paraganglioma

    The New England Journal of Medicine 359:2685–2692.

    https://doi.org/10.1056/NEJMoa0806277

    • PubMed
    • Google Scholar
67. 1. Ladroue C
    2. Hoogewijs D
    3. Gad S
    4. Carcenac R
    5. Storti F
    6. Barrois M
    7. Gimenez-Roqueplo A-P
    8. Leporrier M
    9. Casadevall N
    10. Hermine O
    11. Kiladjian J-J
    12. Baruchel A
    13. Fakhoury F
    14. Bressac-de Paillerets B
    15. Feunteun J
    16. Mazure N
    17. Pouysségur J
    18. Wenger RH
    19. Richard S
    20. Gardie B

    (2012) Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

    Haematologica 97:9–14.

    https://doi.org/10.3324/haematol.2011.044644

    • PubMed
    • Google Scholar
68. 1. Lai Y
    2. Song M
    3. Hakala K
    4. Weintraub ST
    5. Shiio Y

    (2011) Proteomic dissection of the von hippel-lindau (VHL) interactome

    Journal of Proteome Research 10:5175–5182.

    https://doi.org/10.1021/pr200642c

    • PubMed
    • Google Scholar
69. 1. Latif F
    2. Tory K
    3. Gnarra J
    4. Yao M
    5. Duh FM
    6. Orcutt ML
    7. Stackhouse T
    8. Kuzmin I
    9. Modi W
    10. Geil L

    (1993) Identification of the von hippel-lindau disease tumor suppressor gene

    Science 260:1317–1320.

    https://doi.org/10.1126/science.8493574

    • PubMed
    • Google Scholar
70. 1. Li L
    2. Zhang L
    3. Zhang X
    4. Yan Q
    5. Minamishima YA
    6. Olumi AF
    7. Mao M
    8. Bartz S
    9. Kaelin WG Jr

    (2007) Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations

    Molecular and Cellular Biology 27:5381–5392.

    https://doi.org/10.1128/MCB.00282-07

    • PubMed
    • Google Scholar
71. 1. Lindau A

    (1904) ZUR frage der angiomatosis retinae und ihrer hirnkomplikationen

    Acta Ophthalmologica 4:193–226.

    https://doi.org/10.1111/j.1755-3768.1926.tb07786.x

    • Google Scholar
72. 1. Lorenzo FR
    2. Yang C
    3. Ng Tang Fui M
    4. Vankayalapati H
    5. Zhuang Z
    6. Huynh T
    7. Grossmann M
    8. Pacak K
    9. Prchal JT

    (2013) A novel EPAS1/HIF2A germline mutation in A congenital polycythemia with paraganglioma

    Journal of Molecular Medicine 91:507–512.

    https://doi.org/10.1007/s00109-012-0967-z

    • PubMed
    • Google Scholar
73. 1. Lussey-Lepoutre C
    2. Buffet A
    3. Morin A
    4. Goncalves J
    5. Favier J

    (2018) Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis

    Cell and Tissue Research 372:379–392.

    https://doi.org/10.1007/s00441-018-2797-y

    • PubMed
    • Google Scholar
74. 1. Maher ER
    2. Iselius L
    3. Yates JR
    4. Littler M
    5. Benjamin C
    6. Harris R
    7. Sampson J
    8. Williams A
    9. Ferguson-Smith MA
    10. Morton N

    (1991) Von hippel-lindau disease: a genetic study

    Journal of Medical Genetics 28:443–447.

    https://doi.org/10.1136/jmg.28.7.443

    • PubMed
    • Google Scholar
75. 1. Maher ER
    2. Webster AR
    3. Richards FM
    4. Green JS
    5. Crossey PA
    6. Payne SJ
    7. Moore AT

    (1996) Phenotypic expression in von hippel-lindau disease: correlations with germline VHL gene mutations

    Journal of Medical Genetics 33:328–332.

    https://doi.org/10.1136/jmg.33.4.328

    • PubMed
    • Google Scholar
76. 1. Mandriota SJ
    2. Turner KJ
    3. Davies DR
    4. Murray PG
    5. Morgan NV
    6. Sowter HM
    7. Wykoff CC
    8. Maher ER
    9. Harris AL
    10. Ratcliffe PJ
    11. Maxwell PH

    (2002) HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron

    Cancer Cell 1:459–468.

    https://doi.org/10.1016/s1535-6108(02)00071-5

    • PubMed
    • Google Scholar
77. 1. Massfelder T
    2. Lang H
    3. Schordan E
    4. Lindner V
    5. Rothhut S
    6. Welsch S
    7. Simon-Assmann P
    8. Barthelmebs M
    9. Jacqmin D
    10. Helwig J-J

    (2004) Parathyroid hormone-related protein is an essential growth factor for human clear cell renal carcinoma and a target for the von hippel-lindau tumor suppressor gene

    Cancer Research 64:180–188.

    https://doi.org/10.1158/0008-5472.can-03-1968

    • PubMed
    • Google Scholar
78. 1. Maynard MA
    2. Qi H
    3. Chung J
    4. Lee EHL
    5. Kondo Y
    6. Hara S
    7. Conaway RC
    8. Conaway JW
    9. Ohh M

    (2003) Multiple splice variants of the human HIF-3 alpha locus are targets of the von hippel-lindau E3 ubiquitin ligase complex

    The Journal of Biological Chemistry 278:11032–11040.

    https://doi.org/10.1074/jbc.M208681200

    • PubMed
    • Google Scholar
79. 1. Minervini G
    2. Mazzotta GM
    3. Masiero A
    4. Sartori E
    5. Corrà S
    6. Potenza E
    7. Costa R
    8. Tosatto SCE

    (2015) Isoform-specific interactions of the von hippel-lindau tumor suppressor protein

    Scientific Reports 5:12605.

    https://doi.org/10.1038/srep12605

    • PubMed
    • Google Scholar
80. 1. Montani M
    2. Heinimann K
    3. von Teichman A
    4. Rudolph T
    5. Perren A
    6. Moch H

    (2010) VHL-gene deletion in single renal tubular epithelial cells and renal tubular cysts: further evidence for a cyst-dependent progression pathway of clear cell renal carcinoma in von hippel-lindau disease

    The American Journal of Surgical Pathology 34:806–815.

    https://doi.org/10.1097/PAS.0b013e3181ddf54d

    • PubMed
    • Google Scholar
81. 1. Monzon FA
    2. Alvarez K
    3. Peterson L
    4. Truong L
    5. Amato RJ
    6. Hernandez-McClain J
    7. Tannir N
    8. Parwani AV
    9. Jonasch E

    (2011) Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis

    Modern Pathology 24:1470–1479.

    https://doi.org/10.1038/modpathol.2011.107

    • PubMed
    • Google Scholar
82. 1. Morris MR
    2. Hughes DJ
    3. Tian Y-M
    4. Ricketts CJ
    5. Lau KW
    6. Gentle D
    7. Shuib S
    8. Serrano-Fernandez P
    9. Lubinski J
    10. Wiesener MS
    11. Pugh CW
    12. Latif F
    13. Ratcliffe PJ
    14. Maher ER

    (2009)

    Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma

    Anticancer Research 29:4337–4343.

    • PubMed
    • Google Scholar
83. 1. Nargund AM
    2. Pham CG
    3. Dong Y
    4. Wang PI
    5. Osmangeyoglu HU
    6. Xie Y
    7. Aras O
    8. Han S
    9. Oyama T
    10. Takeda S
    11. Ray CE
    12. Dong Z
    13. Berge M
    14. Hakimi AA
    15. Monette S
    16. Lekaye CL
    17. Koutcher JA
    18. Leslie CS
    19. Creighton CJ
    20. Weinhold N
    21. Lee W
    22. Tickoo SK
    23. Wang Z
    24. Cheng EH
    25. Hsieh JJ

    (2017) The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma

    Cell Reports 18:2893–2906.

    https://doi.org/10.1016/j.celrep.2017.02.074

    • PubMed
    • Google Scholar
84. 1. Neumann HP
    2. Wiestler OD

    (1991) Clustering of features and genetics of von hippel-lindau syndrome

    Lancet 338:258.

    https://doi.org/10.1016/0140-6736(91)90401-a

    • PubMed
    • Google Scholar
85. 1. Nielsen SM
    2. Rubinstein WS
    3. Thull DL
    4. Armstrong MJ
    5. Feingold E
    6. Stang MT
    7. Gnarra JR
    8. Carty SE

    (2011a) Genotype-phenotype correlations of pheochromocytoma in two large von hippel-lindau (VHL) type 2A kindreds with different missense mutations

    American Journal of Medical Genetics. Part A 155A:168–173.

    https://doi.org/10.1002/ajmg.a.33760

    • PubMed
    • Google Scholar
86. 1. Nielsen SM
    2. Rubinstein WS
    3. Thull DL
    4. Armstrong MJ
    5. Feingold E
    6. Yip L
    7. Tisherman SA
    8. Carty SE

    (2011b) Long-term outcomes, branch-specific expressivity, and disease-related mortality in von hippel-lindau type 2A

    Familial Cancer 10:701–707.

    https://doi.org/10.1007/s10689-011-9465-7

    • PubMed
    • Google Scholar
87. 1. Ohh M
    2. Yauch RL
    3. Lonergan KM
    4. Whaley JM
    5. Stemmer-Rachamimov AO
    6. Louis DN
    7. Gavin BJ
    8. Kley N
    9. Kaelin WG
    10. Iliopoulos O

    (1998) The von hippel-lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix

    Molecular Cell 1:959–968.

    https://doi.org/10.1016/s1097-2765(00)80096-9

    • PubMed
    • Google Scholar
88. 1. Oliveira JL
    2. Coon LM
    3. Frederick LA
    4. Hein M
    5. Swanson KC
    6. Savedra ME
    7. Porter TR
    8. Patnaik MM
    9. Tefferi A
    10. Pardanani A
    11. Grebe SK
    12. Viswanatha DS
    13. Hoyer JD

    (2018) Genotype-phenotype correlation of hereditary erythrocytosis mutations, a single center experience

    American Journal of Hematology 93:1029–1041.

    https://doi.org/10.1002/ajh.25150

    • Google Scholar
89. 1. Oughtred R
    2. Rust J
    3. Chang C
    4. Breitkreutz B-J
    5. Stark C
    6. Willems A
    7. Boucher L
    8. Leung G
    9. Kolas N
    10. Zhang F
    11. Dolma S
    12. Coulombe-Huntington J
    13. Chatr-Aryamontri A
    14. Dolinski K
    15. Tyers M

    (2021) The biogrid database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions

    Protein Science 30:187–200.

    https://doi.org/10.1002/pro.3978

    • PubMed
    • Google Scholar
90. 1. Pacak K
    2. Jochmanova I
    3. Prodanov T
    4. Yang C
    5. Merino MJ
    6. Fojo T
    7. Prchal JT
    8. Tischler AS
    9. Lechan RM
    10. Zhuang Z

    (2013) New syndrome of paraganglioma and somatostatinoma associated with polycythemia

    Journal of Clinical Oncology 31:1690–1698.

    https://doi.org/10.1200/JCO.2012.47.1912

    • PubMed
    • Google Scholar
91. 1. Pacak K
    2. Chew EY
    3. Pappo AS
    4. Yang C
    5. Lorenzo FR
    6. Wilson MW
    7. Aronow MB
    8. Young JA
    9. Popovic V
    10. Zhuang Z

    (2014) Ocular manifestations of hypoxia-inducible factor-2α paraganglioma-somatostatinoma-polycythemia syndrome

    Ophthalmology 121:2291–2293.

    https://doi.org/10.1016/j.ophtha.2014.06.019

    • PubMed
    • Google Scholar
92. 1. Pang Y
    2. Gupta G
    3. Jha A
    4. Yue X
    5. Wang H
    6. Huynh T-T
    7. Li A
    8. Li L
    9. Baker E
    10. Chew E
    11. Feelders RA
    12. Korpershoek E
    13. Zhuang Z
    14. Yang C
    15. Pacak K

    (2019) Nonmosaic somatic HIF2A mutations associated with late onset polycythemia-paraganglioma syndrome: newly recognized subclass of polycythemia-paraganglioma syndrome

    Cancer 125:1258–1266.

    https://doi.org/10.1002/cncr.31839

    • PubMed
    • Google Scholar
93. 1. Pastore YD
    2. Jelinek J
    3. Ang S
    4. Guan Y
    5. Liu E
    6. Jedlickova K
    7. Krishnamurti L
    8. Prchal JT

    (2003) Mutations in the VHL gene in sporadic apparently congenital polycythemia

    Blood 101:1591–1595.

    https://doi.org/10.1182/blood-2002-06-1843

    • PubMed
    • Google Scholar
94. 1. Percy MJ
    2. Zhao Q
    3. Flores A
    4. Harrison C
    5. Lappin TRJ
    6. Maxwell PH
    7. McMullin MF
    8. Lee FS

    (2006) A family with erythrocytosis establishes A role for prolyl hydroxylase domain protein 2 in oxygen homeostasis

    PNAS 103:654–659.

    https://doi.org/10.1073/pnas.0508423103

    • PubMed
    • Google Scholar
95. 1. Percy MJ
    2. Furlow PW
    3. Beer PA
    4. Lappin TRJ
    5. McMullin MF
    6. Lee FS

    (2007) A novel erythrocytosis-associated PHD2 mutation suggests the location of A HIF binding groove

    Blood 110:2193–2196.

    https://doi.org/10.1182/blood-2007-04-084434

    • PubMed
    • Google Scholar
96. 1. Pritchett TL
    2. Bader HL
    3. Henderson J
    4. Hsu T

    (2015) Conditional inactivation of the mouse von hippel-lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney

    Oncogene 34:2631–2639.

    https://doi.org/10.1038/onc.2014.197

    • Google Scholar
97. 1. Prowse AH
    2. Webster AR
    3. Richards FM
    4. Richard S
    5. Olschwang S
    6. Resche F
    7. Affara NA
    8. Maher ER

    (1997)

    Somatic inactivation of the VHL gene in von hippel-lindau disease tumors

    American Journal of Human Genetics 60:765–771.

    • PubMed
    • Google Scholar
98. 1. Rankin EB
    2. Higgins DF
    3. Walisser JA
    4. Johnson RS
    5. Bradfield CA
    6. Haase VH

    (2005) Inactivation of the arylhydrocarbon receptor nuclear translocator (arnt) suppresses von hippel-lindau disease-associated vascular tumors in mice

    Molecular and Cellular Biology 25:3163–3172.

    https://doi.org/10.1128/MCB.25.8.3163-3172.2005

    • PubMed
    • Google Scholar
99. 1. Rankin EB
    2. Rha J
    3. Unger TL
    4. Wu CH
    5. Shutt HP
    6. Johnson RS
    7. Simon MC
    8. Keith B
    9. Haase VH

    (2008) Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice

    Oncogene 27:5354–5358.

    https://doi.org/10.1038/onc.2008.160

    • PubMed
    • Google Scholar
100. 1. Rechsteiner MP
     2. von Teichman A
     3. Nowicka A
     4. Sulser T
     5. Schraml P
     6. Moch H

     (2011) VHL gene mutations and their effects on hypoxia inducible factor hifα: identification of potential driver and passenger mutations

     Cancer Research 71:5500–5511.

     https://doi.org/10.1158/0008-5472.CAN-11-0757

     • PubMed
     • Google Scholar
101. 1. Rothberg PG
     2. Bradley JF
     3. Baker DW
     4. Huelsman KM

     (2001) Is the P25L a “real” VHL mutation?

     Molecular Diagnosis 6:49–54.

     https://doi.org/10.1054/modi.2001.21637

     • PubMed
     • Google Scholar
102. 1. Schödel J
     2. Oikonomopoulos S
     3. Ragoussis J
     4. Pugh CW
     5. Ratcliffe PJ
     6. Mole DR

     (2011) High-resolution genome-wide mapping of HIF-binding sites by chip-seq

     Blood 117:e207–e217.

     https://doi.org/10.1182/blood-2010-10-314427

     • PubMed
     • Google Scholar
103. 1. Schönenberger D
     2. Harlander S
     3. Rajski M
     4. Jacobs RA
     5. Lundby A-K
     6. Adlesic M
     7. Hejhal T
     8. Wild PJ
     9. Lundby C
     10. Frew IJ

     (2016) Formation of renal cysts and tumors in vhl/trp53-deficient mice requires HIF1α and HIF2α

     Cancer Research 76:2025–2036.

     https://doi.org/10.1158/0008-5472.CAN-15-1859

     • PubMed
     • Google Scholar
104. 1. Schreinemakers JMJ
     2. Zonnenberg BA
     3. Höppener JWM
     4. Hes FJ
     5. Rinkes I
     6. Lips CJM

     (2007) A patient with bilateral pheochromocytoma as part of A von hippel-lindau (VHL) syndrome type 2C

     World Journal of Surgical Oncology 5:1–6.

     https://doi.org/10.1186/1477-7819-5-112

     • PubMed
     • Google Scholar
105. 1. Shen C
     2. Beroukhim R
     3. Schumacher SE
     4. Zhou J
     5. Chang M
     6. Signoretti S
     7. Kaelin WG

     (2011) Genetic and functional studies implicate hif1α as a 14q kidney cancer suppressor gene

     Cancer Discovery 1:222–235.

     https://doi.org/10.1158/2159-8290.CD-11-0098

     • PubMed
     • Google Scholar
106. 1. Stebbins CE
     2. Kaelin WG
     3. Pavletich NP

     (1999) Structure of the VHL-elonginc-elonginb complex: implications for VHL tumor suppressor function

     Science 284:455–461.

     https://doi.org/10.1126/science.284.5413.455

     • PubMed
     • Google Scholar
107. 1. Stickle NH
     2. Chung J
     3. Klco JM
     4. Hill RP
     5. Kaelin WG
     6. Ohh M

     (2004) PVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development

     Molecular and Cellular Biology 24:3251–3261.

     https://doi.org/10.1128/MCB.24.8.3251-3261.2004

     • PubMed
     • Google Scholar
108. 1. Stolle C
     2. Glenn G
     3. Zbar B
     4. Humphrey JS
     5. Choyke P
     6. Walther M
     7. Pack S
     8. Hurley K
     9. Andrey C
     10. Klausner R
     11. Linehan WM

     (1998) Improved detection of germline mutations in the von hippel-lindau disease tumor suppressor gene

     Human Mutation 12:417–423.

     https://doi.org/10.1002/(SICI)1098-1004(1998)12:6<417::AID-HUMU8>3.0.CO;2-K

     • PubMed
     • Google Scholar
109. 1. Taieb D
     2. Barlier A
     3. Yang C
     4. Pertuit M
     5. Tchoghandjian A
     6. Rochette C
     7. Zattara-Canoni H
     8. Figarella-Branger D
     9. Zhuang Z
     10. Pacak K
     11. Metellus P

     (2016) Somatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas

     Journal of Neuro-Oncology 126:473–481.

     https://doi.org/10.1007/s11060-015-1983-y

     • PubMed
     • Google Scholar
110. 1. Tan Q
     2. Kerestes H
     3. Percy MJ
     4. Pietrofesa R
     5. Chen L
     6. Khurana TS
     7. Christofidou-Solomidou M
     8. Lappin TRJ
     9. Lee FS

     (2013) Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation

     The Journal of Biological Chemistry 288:17134–17144.

     https://doi.org/10.1074/jbc.M112.444059

     • PubMed
     • Google Scholar
111. 1. Tang N
     2. Mack F
     3. Haase VH
     4. Simon MC
     5. Johnson RS

     (2006) PVHL function is essential for endothelial extracellular matrix deposition

     Molecular and Cellular Biology 26:2519–2530.

     https://doi.org/10.1128/MCB.26.7.2519-2530.2006

     • PubMed
     • Google Scholar
112. 1. Tarade D
     2. Robinson CM
     3. Lee JE
     4. Ohh M

     (2018) HIF-2α-pvhl complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease

     Nature Communications 9:3359.

     https://doi.org/10.1038/s41467-018-05554-1

     • PubMed
     • Google Scholar
113. 1. Tarhonskaya H
     2. Hardy AP
     3. Howe EA
     4. Loik ND
     5. Kramer HB
     6. McCullagh JSO
     7. Schofield CJ
     8. Flashman E

     (2015) Kinetic investigations of the role of factor inhibiting hypoxia-inducible factor (FIH) as an oxygen sensor

     The Journal of Biological Chemistry 290:19726–19742.

     https://doi.org/10.1074/jbc.M115.653014

     • PubMed
     • Google Scholar
114. 1. Thoma CR
     2. Toso A
     3. Gutbrodt KL
     4. Reggi SP
     5. Frew IJ
     6. Schraml P
     7. Hergovich A
     8. Moch H
     9. Meraldi P
     10. Krek W

     (2009) VHL loss causes spindle misorientation and chromosome instability

     Nature Cell Biology 11:994–1001.

     https://doi.org/10.1038/ncb1912

     • PubMed
     • Google Scholar
115. 1. Turajlic S
     2. Xu H
     3. Litchfield K
     4. Rowan A
     5. Chambers T
     6. Lopez JI
     7. Nicol D
     8. O’Brien T
     9. Larkin J
     10. Horswell S
     11. Stares M
     12. Au L
     13. Jamal-Hanjani M
     14. Challacombe B
     15. Chandra A
     16. Hazell S
     17. Eichler-Jonsson C
     18. Soultati A
     19. Chowdhury S
     20. Rudman S
     21. Lynch J
     22. Fernando A
     23. Stamp G
     24. Nye E
     25. Jabbar F
     26. Spain L
     27. Lall S
     28. Guarch R
     29. Falzon M
     30. Proctor I
     31. Pickering L
     32. Gore M
     33. Watkins TBK
     34. Ward S
     35. Stewart A
     36. DiNatale R
     37. Becerra MF
     38. Reznik E
     39. Hsieh JJ
     40. Richmond TA
     41. Mayhew GF
     42. Hill SM
     43. McNally CD
     44. Jones C
     45. Rosenbaum H
     46. Stanislaw S
     47. Burgess DL
     48. Alexander NR
     49. Swanton C
     50. PEACE
     51. TRACERx Renal Consortium

     (2018) Tracking cancer evolution reveals constrained routes to metastases: tracerx renal

     Cell 173:581–594.

     https://doi.org/10.1016/j.cell.2018.03.057

     • PubMed
     • Google Scholar
116. 1. Wang H
     2. Cui J
     3. Yang C
     4. Rosenblum JS
     5. Zhang Q
     6. Song Q
     7. Pang Y
     8. Fang F
     9. Sun M
     10. Dmitriev P
     11. Gilbert MR
     12. Eisenhofer G
     13. Pacak K
     14. Zhuang Z

     (2019) A transgenic mouse model of pacak

     Cancers 11:E667.

     https://doi.org/10.3390/cancers11050667

     • PubMed
     • Google Scholar
117. 1. Yang H
     2. Minamishima YA
     3. Yan Q
     4. Schlisio S
     5. Ebert BL
     6. Zhang X
     7. Zhang L
     8. Kim WY
     9. Olumi AF
     10. Kaelin WG Jr

     (2007) PVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappab agonist card9 by CK2

     Molecular Cell 28:15–27.

     https://doi.org/10.1016/j.molcel.2007.09.010

     • PubMed
     • Google Scholar
118. 1. Yang C
     2. Zhuang Z
     3. Fliedner SMJ
     4. Shankavaram U
     5. Sun MG
     6. Bullova P
     7. Zhu R
     8. Elkahloun AG
     9. Kourlas PJ
     10. Merino M
     11. Kebebew E
     12. Pacak K

     (2015) Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia

     Journal of Molecular Medicine 93:93–104.

     https://doi.org/10.1007/s00109-014-1205-7

     • PubMed
     • Google Scholar
119. 1. Zhang J
     2. Wu T
     3. Simon J
     4. Takada M
     5. Saito R
     6. Fan C
     7. Liu X-D
     8. Jonasch E
     9. Xie L
     10. Chen X
     11. Yao X
     12. Teh BT
     13. Tan P
     14. Zheng X
     15. Li M
     16. Lawrence C
     17. Fan J
     18. Geng J
     19. Liu X
     20. Hu L
     21. Wang J
     22. Liao C
     23. Hong K
     24. Zurlo G
     25. Parker JS
     26. Auman JT
     27. Perou CM
     28. Rathmell WK
     29. Kim WY
     30. Kirschner MW
     31. Kaelin WG Jr
     32. Baldwin AS
     33. Zhang Q

     (2018) VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma

     Science 361:290–295.

     https://doi.org/10.1126/science.aap8411

     • PubMed
     • Google Scholar
120. 1. Zimmer M
     2. Doucette D
     3. Siddiqui N
     4. Iliopoulos O

     (2004) Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL−/− tumors1 1 NIH grant R29CA78358-06 (OI), bertucci fund for urologic malignancies (OI), david P. foss fund (OI), and VHL family alliance 2003 award (MZ)

     Molecular Cancer Research 2:89–95.

     https://doi.org/10.1158/1541-7786.89.2.2

     • Google Scholar

Author details

1. Michael Ohh

   1. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
   2. Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   michael.ohh@utoronto.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7600-4751

2. Cassandra C Taber

   Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Fraser G Ferens

   1. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
   2. Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6686-1183

4. Daniel Tarade

   Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada

   Contribution

   Conceptualization, Data curation, Writing – original draft, Writing – review and editing

   For correspondence

   daniel.tarade@mail.utoronto.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7029-9640

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