|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 24 (December 15), 2004: pp. 4991-5004 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.061
Role of VHL Gene Mutation in Human CancerFrom the Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Address reprint requests to William G. Kaelin Jr, MD, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; e-mail: william_kaelin{at}dfci.harvard.edu
Germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes the von Hippel-Lindau hereditary cancer syndrome, and somatic mutations of this gene have been linked to the development of sporadic hemangioblastomas and clear-cell renal carcinomas. The VHL tumor suppressor protein (pVHL), through its oxygen-dependent polyubiquitylation of hypoxia-inducible factor (HIF), plays a central role in the mammalian oxygen-sensing pathway. This interaction between pVHL and HIF is governed by post-translational prolyl hydroxylation of HIF in the presence of oxygen by a conserved family of Egl-nine (EGLN) enzymes. In the absence of pVHL, HIF becomes stabilized and is free to induce the expression of its target genes, many of which are important in regulating angiogenesis, cell growth, or cell survival. Moreover, preliminary data indicate that HIF plays a critical role in pVHL-defective tumor formation, raising the possibility that drugs directed against HIF or its downstream targets (such as vascular endothelial growth factor) might one day play a role in the treatment of hemangioblastoma and renal cell carcinoma. On the other hand, clear genotype-phenotype correlations are emerging in VHL disease and can be rationalized if pVHL has functions separate from its control of HIF.
von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by CNS and retinal hemangioblastomas, clear-cell renal carcinomas, and pheochromocytomas. It was first described in the medical literature in 1894 by Treacher Collins, who detailed his histopathological observations on bilateral vascular growths in the retinas of two siblings.1 A decade later, Eugene von Hippel, a German ophthalmologist, described another family in which individuals developed similar blood vessel tumors of the retina and coined the term angiomatosis retinae.2 The Swedish pathologist Arvid Lindau, while writing a thesis on cystic lesions of the cerebellum, noted that these retinal lesions were associated with an increased risk of developing hemangioblastomas of the brain and spinal cord.3 Although previously referred to as "Lindau's disease," Charles Davison coined the eponym "von Hippel-Lindau disease" in 1936.4 Since then, a variety of other lesions have also been associated with VHL disease including visceral cysts, particularly of the pancreas and kidneys, and other tumors such as clear-cell renal carcinomas, pheochromocytomas, endolymphatic sac tumors of the inner ear, epididymal and broad ligament cystadenomas, and islet-cell tumors of the pancreas.5 VHL disease affects approximately 1 in 35,000 individuals and is transmitted in an autosomal dominant manner.
The VHL gene was mapped by linkage analysis to the short arm of chromosome 3 in 1988 by Seizinger et al.6 It was isolated in 1993 using a positional cloning strategy through an international collaboration led by Eamon Maher (University of Cambridge, England), Michael Lerman, Marston Linehan, and Berton Zbar (National Cancer Institute, United States).7 The VHL gene consists of three exons and is widely expressed in both fetal and adult tissues. In particular, expression of the VHL gene is not restricted to the organs affected in VHL disease.7-10 Individuals with VHL disease carry one wild-type VHL allele and one inactivated VHL allele. In other words, VHL patients are VHL heterozygotes. Tumor or cyst development in VHL disease is linked to somatic inactivation or loss of the remaining wild-type VHL allele. In earlier studies, VHL mutations were not identifiable in up to 20% of patients who carried a clinical diagnosis of VHL disease. However, a more recent report indicates that VHL gene abnormalities can be detected in such patients if conventional methods, such as direct DNA sequencing and Southern Blot Analysis, are supplemented with quantitative Southern Blotting and fluorescence in situ hybridization (FISH).11 Approximately 20% to 37% of VHL patients have large or partial germline deletions, 30% to 38% have missense mutations, and 23% to 27% have nonsense or frameshift mutations.5,11 In general, VHL mutations are extremely heterogeneous and are distributed throughout the coding sequence, except that intragenic missense mutations are rarely seen within the first 50 codons.12 In total, more than 150 different germline VHL mutations linked to VHL disease have been reported.12 Listing of VHL mutations can be viewed at two Internet sites (http://www.umd.necker.fr:2005 and http://web.ncifcrf.gov).
Clear genotype-phenotype correlations are emerging in VHL disease and may be useful in counseling patients regarding the risk of developing specific VHL-associated tumors such as pheochromocytoma. Clinically, VHL families can be subdivided based on the presence (type 2) or absence (type 1) of pheochromocytomas (Table 1). Type 2 families can be further subclassified based on their risk of developing renal cell carcinoma: low risk (type 2A) or high risk (type 2B). Some type 2 families develop pheochromocytoma without the other classical stigmata of VHL disease (type 2C). Families at risk for developing pheochromocytoma (type 2 families) almost invariably harbor VHL missense mutations, in contrast to families without pheochromocytomas (type 1 families). Type 1 families frequently harbor VHL deletions or truncation mutations.12,13 It is presumed that the genotype-phenotype correlations in VHL disease reflect the degree to which the functions of the VHL gene product, pVHL, are quantitatively or qualitatively altered by different VHL mutations (discussed later).
VHL disease is one of several hereditary cancer syndromes associated with an increased risk of renal cell carcinoma (Table 2). These syndromes can usually be distinguished from VHL disease based on tumor histology and coexistent clinical features. Hereditary papillary renal carcinoma, which is distinct from the clear-cell variant associated with VHL disease, has been linked to germline gain of function mutations of the c-Met proto-oncogene or loss of function mutations of the Fumarate Hydratase gene.14,15 Fumarate Hydratase mutations are also associated with an increased risk of cutaneous leiomyomata and uterine fibroids. Birt-Hogg-Dube syndrome, caused by germline loss of function mutations of the BHD gene, is characterized by fibrofolliculomas, lung cysts (with or without spontaneous pneumothorax), and a spectrum of renal carcinomas of varying histological subtypes (chromophobe, oncocytoma, clear-cell, or papillary).16,17 Bin Teh et al have also described a familial clear-cell renal carcinoma syndrome that is not linked to VHL mutation and whose cause is currently unknown.18
Familial pheochromocytoma (or paraganglioma) is a feature not only of VHL disease but also of neurofibromatosis type 1, which is caused by loss of function mutation of the NF1 gene, and multiple endocrine neoplasia type 2 (MEN2), which is caused by gain of function mutation of the RET gene.19 Familial pheochromocytoma has also been linked to germline inactivating mutations affecting specific succinate dehydrogenase subunits (B, C, D; Table 3).20,21 Interestingly, approximately 25% of apparently sporadic pheochromocytomas are actually due to an occult germline mutation in either VHL, RET, or one of these succinate dehydrogenase genes.22 In contrast, germline VHL mutations are uncommon in patients who present with seemingly sporadic clear-cell renal carcinoma or hemangioblastoma (Table 4).
In keeping with the Knudson two-hit model, biallelic VHL inactivation (as a result of mutation or hypermethylation) is common in both sporadic hemangioblastomas and sporadic clear-cell renal carcinomas (Table 4).52 VHL seems to be mutated somatically in approximately 50%, and hypermethylated in another 10% to 20% of sporadic clear-cell renal carcinomas. However, mutation or hypermethylation of the VHL gene is rarely detected in other histologic subtypes of renal cell carcinoma. Similarly, VHL has been found to be mutated somatically in approximately 30% of sporadic hemangioblastomas. In contrast to renal cell carcinoma, however, hypermethylation of VHL in sporadic hemangioblastomas has not been detected to date (Table 4). In the setting of sporadic tumors, both the first "hit" and second "hit" occur somatically (that is, after conception) rather than in the germline. Germline VHL mutations are rarely discovered in patients who present with seemingly sporadic clear-cell renal carcinoma or hemangioblastoma, in contrast to patients who present with seemingly sporadic pheochromocytoma. Surprisingly, somatic VHL mutations are rare in truly sporadic pheochromocytoma (that is, in pheochromocytomas that are not linked to germline VHL mutations), despite the increased risk of this tumor in VHL disease (Table 4). Among several possibilities, this might suggest that the development of pheochromocytoma in the setting of VHL disease is due to inactivation of VHL during a critical developmental window or is linked to a "field defect" (that is, a defect shared by all the cells in a tissue rather than an individual clone) resulting from VHL haploinsufficiency. Studies examining a variety of other sporadic tumors, including breast, colon, lung, and prostate cancers, have found that somatic VHL mutations are rare in histological tumor types that are not observed in VHL disease.23,24,53,54
The VHL mRNA encodes a protein (pVHL) that contains 213 amino acid residues and migrates with an apparent molecular weight of  24 to 30 kDa (VHL30).9 The primary sequence of pVHL does not closely resemble that of other known proteins. A second pVHL isoform of approximately 19kDa (VHL19) is produced as a result of internal translational initiation at an in-frame start codon (ATG) at codon 54.55-57 Both isoforms appear to retain tumor suppressor activity, perhaps accounting for the paucity of VHL missense mutations affecting the first 50 amino acid residues (described earlier). For simplicity, the term "pVHL" is used when referring to both isoforms generically. pVHL shuttles between the nucleus and cytoplasm.58-61 This shuttling by pVHL is important for its tumor suppressor function. There is some suggestion that VHL30 resides primarily in the cytoplasm, while VHL19 is located primarily in the nucleus, suggesting that the functions of the two isoforms, while overlapping, are not identical.56,62
The tumors linked to VHL inactivation are often highly vascular and can overproduce angiogenic factors such as vascular endothelial growth factor (VEGF).63-69 In addition, renal cell carcinoma, hemangioblastomas, and pheochromocytomas have been associated with paraneoplastic erythrocytosis due to erythropoeitin (Epo) overproduction.70-73 VEGF and Epo mRNAs are prototypical hypoxia-inducible mRNAs (that is, these mRNAs are normally induced under conditions characterized by inadequate oxygenation). These considerations led to the discovery that cells lacking pVHL constitutively overproduce hypoxia-inducible mRNAs and that restoration of pVHL function results in down-regulation of hypoxia-inducible mRNAs in the presence of oxygen.66,74-77 Thus, overproduction of hypoxia-inducible mRNAs is a hallmark of pVHL-defective cells.
Early biochemical studies revealed that pVHL forms a multiprotein complex that contained two proteins called Elongin B and Elongin C (Fig 1).78-80 Later, two additional components of the pVHL complex, called Cul281,82 and Rbx1 (also called ROC1 or Hrt1),83 were discovered. Elongin C and Cul2 were noted to be similar to individual components (Skp1 and Cdc53, respectively) of multiprotein complexes in yeast, called SCF complexes (Skp1, Cdc53, F-box protein).81,82,84 SCF complexes target specific proteins for degradation. In particular, SCF complexes orchestrate a post-translational modification, called polyubiquitylation (for this reason, these enzymes are often referred to as ubiquitin ligases), of their substrates. The presence of a polyubiquitin tail serves as a signal or "flag" for the substrate to be degraded by another multiprotein complex, called the proteasome. In such SCF complexes, the F-box protein serves as the substrate-binding module and thereby confers specificity on the SCF complex.85
The three-dimensional structure of pVHL bound to Elongin B and Elongin C confirmed that Elongin C, as suspected, resembled Skp1. Moreover, it revealed that the region of pVHL that binds directly to Elongin C loosely resembles an F-box. Therefore the hypothesis emerged that the pVHL complex, like SCF complexes in yeast, might be a ubiquitin ligase.86 In keeping with this idea, two groups soon showed that partially purified pVHL complexes, recovered by immunoprecipitation using monoclonal antibodies, contained a ubiquitin ligase activity.87,88
Many of the genes that are regulated by hypoxia, including the previously mentioned VEGF and Epo, are under the control of a transcription factor called hypoxia-inducible factor (HIF). HIF is made up of two nonidentical subunits (an alpha subunit and a beta subunit) and binds to specific DNA sequences, whereupon it can activate transcription. There are three HIF  genes in the human genome and three HIFß genes (also called the aryl hydrocarbon receptor nuclear translocators [ARNT]).89 For simplicity, the HIF and HIFß family members will be referred to generically as HIF and HIFß, respectively. HIFß is a stable protein, while the HIF proteins are highly unstable if oxygen is present. Hence, formation of an active HIF heterodimer is restricted to hypoxic conditions.
In 1999, Maxwell et al showed that cells lacking pVHL fail to degrade HIF
The stabilization of HIF that normally occurs under hypoxic conditions implied that the binding of pVHL to HIF, or the functional consequences thereof, was oxygen dependent. Earlier studies had identified a subdomain of HIF1, sometimes called the oxygen-dependent degradation domain (ODD), that was sufficient to confer instability in the presence of oxygen.95-97 This region of HIF1 overlaps one of its two transactivation domains (called the NTAD and CTAD for N-terminal and C-terminal transactivation domain, respectively), which are the regions responsible for activating transcription once recruited to DNA (Fig 1). Three groups independently showed that HIF1 must undergo an oxygen-dependent posttranslational modification to be recognized by pVHL.98-100 In particular, binding by pVHL is linked to hydroxylation of evolutionarily conserved proline residues (technically, prolyl residues since the proline amino acids are incorporated into a protein) within the HIF1 ODD98-101 (hydroxylation of equivalent prolyl residues takes place in HIF2 and HIF3).102 The three-dimensional crystal structure of HIF1 bound to pVHL reveals that the prolyl hydroxyl group forms critical hydrogen bonds with two hydrophilic residues within the otherwise hydrophobic pVHL substrate-binding domain.103,104
Studies in model organisms (C elegans and Drosophila) led to the identification of the HIF prolyl hydroxylase gene, called Egl-9 (so named because it was the ninth gene isolated in an earlier genetic screen for egg laying defective C elegans mutants).105,106 Mammalian cells contain three genes (EGLN1, EGLN2, and EGLN3) that are ancestrally related to Egl-9, and their protein products are all capable of hydroxylating HIF
Activation of gene expression (transactivation) by the HIF1
Given the role of pVHL in oxygen sensing, it is interesting to note that mutations affecting fumarate hydratase and succinate dehydrogenase can, like VHL mutations, give rise to hereditary renal cancer (fumarate hydratase) or pheochromocytoma (succinate dehydrogenase). These two enzymes catalyze sequential steps in the mitochondrial tricarboxylic acid cycle, which is used to generate ATP when oxygen is available. Germline succinate dehydrogenase mutations were originally described in a subset of families with head and neck paragangliomas, particularly of the carotid body.20 The carotid body acts as an organismal oxygen sensor and is the most common site for head and neck paragangliomas.115 Intriguingly, the incidence of carotid body tumors is also increased in individuals living at high altitudes (and who are thus chronically hypoxic).116 Hypoxia affects mitochondrial function. Conversely, there is evidence that mitochondria modulate the cellular response to hypoxia.117 Collectively, these observations suggest that loss of pVHL, fumarate hydratase, or succinate dehydrogenase affect a common hypoxia-responsive pathway, though the precise nature of this pathway remains obscure. In this regard, it is perhaps noteworthy that the HIF prolyl hydroxylase belongs to a superfamily of enzymes that require oxygen and that generate succinate as an enzymatic byproduct.118 It is conceivable that accumulation of succinate inhibits hydroxylase activity, thereby mimicking a hypoxic response. In support of this idea, increased levels of HIF and HIF target genes were observed in carotid body paragangliomas linked to SDH mutations.119,120
Genotype-phenotype correlations in VHL disease suggest that pVHL has functions independent of its role in HIF regulation. First, pVHL mutants linked to type 2C disease seem to retain the ability to bind and polyubiquitylate HIF, suggesting that pheochromocytoma development in this setting is linked to gain or loss of a non-HIF pVHL function.94,121 Second, pVHL mutants linked to type 2A and type 2B VHL disease share an inability to properly regulate HIF, suggesting that the integrity of a second pVHL function modifies the risk of renal cell carcinoma. Third, patients with Chuvash polycythemia, which is a hereditary polycythemia syndrome caused by homozygosity for a hypomorphic VHL allele (VHL R200W), do not appear to be tumor prone. This could reflect the fact that Chuvash pVHL R200W retains partial HIF polyubiquitylation activity, but could also indicate that it retains other, as yet unidentified, pVHL functions that suppress tumor formation.122,123 The existence of HIF-independent pVHL functions would offer one potential explanation for the observation that forced activation of HIF target genes, in the tissues examined to date, has not led to tumor formation. Overexpression of nondegradable forms of HIF, or HIF-like proteins, in mouse skin and rabbit musculature using a variety of approaches instead led to the proliferation of normal-appearing blood vessels.124-126 In keeping with these ideas, gene expression profiling studies suggest that pVHL has HIF-independent functions.127,128 Moreover, a number of other pVHL-binding partners, including potential substrates, have been identified. Indeed, pVHL is reported to ubiquitylate proteins such as atypical protein kinase C129-132; a family of deubiquitylating enzymes named VHL-interacting deubiquitinating enzyme-1 and 2 (VDU1 and VDU2)133,134; and the hyperphosphorylated form of Rpb1, a subunit of RNA polymerase II.135 pVHL has been reported to bind directly to the plant homeodomain protein Jade-1136 and to a KRAB-A domain–containing protein (VHLaK). The latter may cooperate with pVHL to repress HIF-dependent transcription.137 In addition, pVHL has been implicated in diverse cellular processes (described following two sections) including regulation of the extracellular matrix (ECM), cytoskeletal stability, cell-cycle control, and differentiation, though the degree to which these different phenotypes are HIF-dependent and HIF-independent is still unclear.
Early experiments showed that pVHL bound directly to fibronectin, a glycoprotein that interacts with integrins to bridge cells to the structural proteins of the ECM.138 The association between pVHL and fibronectin seems to take place in association with the endoplasmic reticulum. Cells lacking pVHL do not deposit a proper extracellular fibronectin matrix, and this defect can be corrected by restoring pVHL function.138,139 How, mechanistically, the physical association of pVHL with fibronectin affects the fate of secreted fibronectin remains unclear. One study suggested that the defect in ECM formation in pVHL-defective cells was an indirect consequence of altered integrin expression.140 Cells lacking pVHL are also more invasive and secrete higher levels of several matrix metalloproteases (enzymes able to degrade the basement membrane and ECM) and lower levels of a matrix metalloprotease antagonist called TIMP-2 (tissue inhibitor of metalloproteinase 2)141 compared with their wild-type counterparts. Epithelial cell behavior is clearly influenced by interactions with the ECM. Therefore, altered ECM production may contribute to tumorigenesis following pVHL inactivation. In keeping with this idea, pVHL-defective cells, in comparison with their wild-type counterparts, demonstrate increased proliferation and decreased differention when grown on specific matrices (such as matrigel or collagen type I) or as three-dimensional spheroids.139,142 A recent report showed that pVHL also interacts with the cytoskeleton, binding directly to microtubules and inhibiting their depolymerization.62 Interestingly, this function may be independent of E3 ubiquitin ligase formation, since a pVHL mutant lacking the elongin C binding domain was still capable of stabilizing microtubules. Moreover, this activity seemed to distinguish type 2A and type 2B pVHL mutants.62
Cells deficient in wild-type pVHL are unable to exit the cell cycle under certain experimental conditions, such as growth in low serum.142,143 This ability to exit the cell cycle can be restored by reintroduction of wild-type pVHL. Control of the cell cycle by pVHL is likely to be multifactorial. Two recent reports implicate pVHL as a negative regulator of cyclin D1,144,145 which is a mitogen. Whether cyclin D1 is regulated by HIF is not clear at present. pVHL also negatively regulates transforming growth factor alpha (TGF ), recently described as a HIF target gene.146 Intriguingly, renal tubular epithelial cells are particularly sensitive to the mitogenic effects of this cytokine.147,148
VHL–/– mice die during early embryogenesis, due to placental insufficiency.149 An early report indicated that VHL+/– mice develop normally without evidence of tumor formation.149 However, a second report, using a second independently derived VHL+/– mouse strain indicated that such mice have a normal life span but develop multiple vascular tumors in the liver, which loosely resemble hemangioblastomas and overexpress HIF target genes implicated in their human counterparts.150 Similar liver lesions were observed, with higher penetrance and shorter latency, following conditional inactivation of VHL in the liver using Cre recombinase enzyme under the control of a hepatocyte-specific promoter.150
Hemangioblastomas The most common manifestations of VHL disease are retinal and CNS hemangioblastomas. Histological examination of these hemangioblastomas reveals a mixture of lipid-laden "stromal cells," endothelial cells, pericytes, and mast cells (Fig 2). The embryological origin of these stromal cells remains undefined. However, tissue microdissection, in situ hybridization, and immunohistochemical studies indicate that it is these cells, rather than the vascular components, that lack wild-type pVHL and that consequently overproduce HIF and its target gene products.25,64,151,152 It seems likely that overexpression of HIF targets such as VEGF and platelet-derived growth factor B (PDGF B) is responsible for the hypervascularity of these lesions since VEGF and PDGF B are potent mitogens for endothelial cells and pericytes, repectively. In addition, these stromal cells overproduce both TGF and its receptor, epidermal growth factor receptor, which suggests the establishment of an autocrine loop.63,153
It is not yet clear whether mutations at non-VHL loci are required, in addition to VHL inactivation, for hemangioblastoma development. In one mouse model, forced activation of VEGF in the brain was sufficient to cause "hemangioblastoma-like" lesions in the brain.154 In addition, inactivation of VHL in mice is sufficient to form hemangioblastoma-like tumors of the liver, as described earlier.150 Collectively, these studies suggest that VHL inactivation is sufficient for the development of CNS and retinal hemangioblastomas.
Although it has not been formally proven that inhibition of HIF is sufficient to alter the growth of VHL–/– tumors, it seems reasonable given the above considerations, to treat hemangioblastomas with agents that block HIF or its downstream targets. Two groups have now shown that inhibition of HIF2
There have been case reports on the use of targeted therapy for VHL-associated hemangioblastomas. One VHL patient with an optic nerve hemangioblastoma had a dramatic and sustained improvement in her visual acuity and an expansion of her visual field following treatment with SU5416, which is an inhibitor of the VEGF receptor KDR.158 Direct visualization of the tumor, however, did not show appreciable change in its size, leading the authors to conjecture that the clinical improvements were due to decreased peritumoral edema as a consequence of blocking the vascular permeability effects of VEGF.158 In a second report, three patients with VHL-associated CNS hemangioblastomas were also treated with SU5416. Interestingly, all three patients developed polycythemia without demonstrable changes in the size of their tumors 8 to 10 weeks after initiation of therapy.159 The mechanism of this polycythemia was not elucidated, but it might, in theory, have been due to increased tumor hypoxia. Another VHL patient with a progressive metastatic cerebellar hemangioblastoma was treated with OSI-774 (Tarceva; OSI Pharmaceuticals, Melville, NY), a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. This patient had subjective improvement in their neurological symptoms and remained on study for 9 months until clinical progression.160
Renal Cell Carcinoma
To better define the role of HIF in VHL–/– tumors, two groups asked whether HIF Collectively, these findings support the treatment of kidney cancer with the same types of agents described above in the context of hemangioblastoma. VEGF inhibitors have shown activity in preclinical renal cell carcinoma models and are currently being tested in humans.170 In one phase II study, a neutralizing VEGF antibody led to a significant improvement in time to progression in patients with metastatic renal carcinoma.171
Pheochromocytoma
Many of the initial hypotheses and discoveries related to the functions of pVHL were grounded in careful clinical observations made by physicians. During the past decade, the scientific study of VHL has given us insights into not only the molecular basis for VHL disease but also the discovery of critical components of the mammalian oxygen-sensing pathway. The importance of HIF with respect to pVHL-defective tumor formation is already providing a rationale for testing small molecule inhibitors of HIF-responsive growth factors as potential treatments for renal cell carcinoma and hemangioblastoma. However, many important questions remain. It is currently unknown why VHL mutations are linked to such a highly restricted subset of tumor types. Nor is it understood why specific VHL mutations are associated with different site-specific tumor risks. The answers to these questions may lie in understanding whether pVHL has tumor suppressive functions unrelated to its ability to inhibit HIF, and, if so, how the loss of these activities conspires with HIF to promote tumor growth. In addition, it will be important to identify the other genes that, when mutated, cooperate with VHL inactivation to cause cancer in specific tissues such as the kidney. As these questions are answered and our understanding of pVHL function becomes clearer, physicians and patients alike will hopefully benefit from their original contributions to the discovery and description of VHL disease.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Collins E: Intra-ocular growths (two cases, brother and sister, with peculiar vascular new growth, probably retinal, affecting both eyes). Trans Ophthalmol Soc U K 14:141-149, 1894 2. Hippel Ev: Ueber eine sehr seltene erkrankung der nethaut. Graefe Arch Ophthalmol 59:83-106, 1904[CrossRef] 3. Lindau A: Zur frage der angiomatosis retinai und ihrer hirncomplikation. Acta Ophthalmol 4:193-226, 1927 4. Davison C, Brock S, Cyke CG: Retinal and central nervous hemangioblastomatosis with visceral changes (von Hippel-Lindau's disease). Bull Neurol Inst New York 5:72-93, 1936 5. Maher ER, Kaelin WG Jr: von Hippel-Lindau disease. Medicine (Baltimore) 76:381-391, 1997[CrossRef][Medline] 6. Seizinger BR, Rouleau GA, Ozelius LJ, et al: Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 332:268-269, 1988[CrossRef][Medline]
7. Latif F, Tory K, Gnarra J, et al: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317-1320, 1993 8. Renbaum P, Duh FM, Latif F, et al: Isolation and characterization of the full-length 3' untranslated region of the human von Hippel-Lindau tumor suppressor gene. Hum Genet 98:666-671, 1996[CrossRef][Medline] 9. Iliopoulos O, Kibel A, Gray S, et al: Tumour suppression by the human von Hippel-Lindau gene product. Nat Med 1:822-826, 1995[CrossRef][Medline]
10. Richards FM, Schofield PN, Fleming S, et al: Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis. Hum Mol Genet 5:639-644, 1996 11. Stolle C, Glenn G, Zbar B, et al: Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 12:417-423, 1998[CrossRef][Medline] 12. Zbar B, Kishida T, Chen F, et al: Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 8:348-357, 1996[CrossRef][Medline] 13. Chen F, Kishida T, Yao M, et al: Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: Correlations with phenotype. Hum Mutat 5:66-75, 1995[CrossRef][Medline] 14. Schmidt L, Duh FM, Chen F, et al: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16:68-73, 1997[CrossRef][Medline] 15. Tomlinson IP, Alam NA, Rowan AJ, et al: Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30:406-410, 2002[CrossRef][Medline] 16. Nickerson ML, Warren MB, Toro JR, et al: Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2:157-164, 2002[CrossRef][Medline] 17. Pavlovich CP, Walther MM, Eyler RA, et al: Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol 26:1542-1552, 2002[CrossRef][Medline] 18. Teh BT, Giraud S, Sari NF, et al: Familial non-VHL non-papillary clear-cell renal cancer. Lancet 349:848-849, 1997[CrossRef][Medline]
19. Maher ER, Eng C: The pressure rises: Update on the genetics of phaeochromocytoma. Hum Mol Genet 11:2347-2354, 2002
20. Baysal BE, Ferrell RE, Willett-Brozick JE, et al: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848-851, 2000 21. Milunsky JM, Maher TA, Michels VV, et al: Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. Am J Med Genet 100:311-314, 2001[CrossRef][Medline]
22. Neumann HP, Bausch B, McWhinney SR, et al: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459-1466, 2002 23. Gnarra JR, Tory K, Weng Y, et al: Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 7:85-90, 1994[CrossRef][Medline] 24. Whaley JM, Naglich J, Gelbert L, et al: Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinoma. Am J Hum Genet 55:1092-1102, 1994[Medline]
25. Lee JY, Dong SM, Park WS, et al: Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res 58:504-508, 1998
26. Shuin T, Kondo K, Torigoe S, et al: Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res 54:2852-2855, 1994
27. Foster K, Prowse A, van den Berg A, et al: Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet 3:2169-2173, 1994 28. Kenck C, Wilhelm M, Bugert P, et al: Mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinomas. J Pathol 179:157-161, 1996[CrossRef][Medline] 29. Gallou C, Joly D, Mejean A, et al: Mutations of the VHL gene in sporadic renal cell carcinoma: Definition of a risk factor for VHL patients to develop an RCC. Hum Mutat 13:464-475, 1999[CrossRef][Medline]
30. Brauch H, Weirich G, Brieger J, et al: VHL alterations in human clear cell renal cell carcinoma: Association with advanced tumor stage and a novel hot spot mutation. Cancer Res 60:1942-1948, 2000 31. Kondo K, Yao M, Yoshida M, et al: Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: Relationship to clinicopathological parameters. Genes Chromosomes Cancer 34:58-68, 2002[CrossRef][Medline] 32. Igarashi H, Esumi M, Ishida H, et al: Vascular endothelial growth factor overexpression is correlated with von Hippel-Lindau tumor suppressor gene inactivation in patients with sporadic renal cell carcinoma. Cancer 95:47-53, 2002[CrossRef][Medline] 33. Hamano K, Esumi M, Igarashi H, et al: Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene in sporadic renal cell carcinoma. J Urol 167:713-717, 2002[CrossRef][Medline] 34. Herman JG, Latif F, Weng Y, et al: Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 91:9700-9704, 1994 35. Clifford SC, Prowse AH, Affara NA, et al: Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: Evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer 22:200-209, 1998[CrossRef][Medline] 36. Brauch H, Bohm J, Hofler H: [Hippel-Lindau syndrome and sporadic renal cell carcinomas. Pathogenesis, morphologic spectrum and molecular genetics]. Pathologe 16:321-327, 1995[CrossRef][Medline]
37. Kanno H, Kondo K, Ito S, et al: Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res 54:4845-4847, 1994 38. Oberstrass J, Reifenberger G, Reifenberger J, et al: Mutation of the Von Hippel-Lindau tumour suppressor gene in capillary haemangioblastomas of the central nervous system. J Pathol 179:151-156, 1996[CrossRef][Medline] 39. Tse JY, Wong JH, Lo KW, et al: Molecular genetic analysis of the von Hippel-Lindau disease tumor suppressor gene in familial and sporadic cerebellar hemangioblastomas. Am J Clin Pathol 107:459-466, 1997[Medline] 40. Olschwang S, Richard S, Boisson C, et al: Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. Hum Mutat 12:424-430, 1998[CrossRef][Medline]
41. Glasker S, Bender BU, Apel TW, et al: Reconsideration of biallelic inactivation of the VHL tumour suppressor gene in hemangioblastomas of the central nervous system. J Neurol Neurosurg Psychiatry 70:644-648, 2001 42. Gijtenbeek JM, Jacobs B, Sprenger SH, et al: Analysis of von hippel-lindau mutations with comparative genomic hybridization in sporadic and hereditary hemangioblastomas: Possible genetic heterogeneity. J Neurosurg 97:977-982, 2002[Medline] 43. Singh AD, Ahmad NN, Shields CL, et al: Solitary retinal capillary hemangioma: Lack of genetic evidence for von Hippel-Lindau disease. Ophthalmic Genet 23:21-27, 2002[CrossRef][Medline] 44. Webster AR, Maher ER, Bird AC, et al: A clinical and molecular genetic analysis of solitary ocular angioma. Ophthalmology 106:623-629, 1999[CrossRef][Medline] 45. Bar M, Friedman E, Jakobovitz O, et al: Sporadic phaeochromocytomas are rarely associated with germline mutations in the von Hippel-Lindau and RET genes. Clin Endocrinol (Oxf) 47:707-712, 1997[CrossRef][Medline]
46. Eng C, Crossey PA, Mulligan LM, et al: Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. J Med Genet 32:934-937, 1995
47. Hofstra RM, Stelwagen T, Stulp RP, et al: Extensive mutation scanning of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases. J Clin Endocrinol Metab 81:2881-2884, 1996
48. Brauch H, Hoeppner W, Jahnig H, et al: Sporadic pheochromocytomas are rarely associated with germline mutations in the VHL tumor suppressor gene or the ret protooncogene. J Clin Endocrinol Metab 82:4101-4104, 1997 49. van der Harst E, de Krijger RR, Dinjens WN, et al: Germline mutations in the vhl gene in patients presenting with phaeochromocytomas. Int J Cancer 77:337-340, 1998[CrossRef][Medline]
50. Bender BU, Gutsche M, Glasker S, et al: Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. J Clin Endocrinol Metab 85:4568-4574, 2000 51. Dannenberg H, De Krijger RR, van der Harst E, et al: Von Hippel-Lindau gene alterations in sporadic benign and malignant pheochromocytomas. Int J Cancer 105:190-195, 2003[CrossRef][Medline] 52. Knudson AG Jr, Strong LC, Anderson DE: Heredity and cancer in man. Prog Med Genet 9:113-158, 1973[Medline] 53. Foster K, Osborne RJ, Huddart RA, et al: Molecular genetic analysis of the von Hippel-Lindau disease (VHL) tumour suppressor gene in gonadal tumours. Eur J Cancer 31A:2392-2395, 1995 54. Zhuang Z, Emmert-Buck MR, Roth MJ, et al: Von Hippel-Lindau disease gene deletion detected in microdissected sporadic human colon carcinoma specimens. Hum Pathol 27:152-156, 1996[CrossRef][Medline]
55. Schoenfeld A, Davidowitz EJ, Burk RD: 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 U S A 95:8817-8822, 1998
56. Iliopoulos O, Ohh M, Kaelin WG Jr: pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci U S A 95:11661-11666, 1998 57. Blankenship C, Naglich JG, Whaley JM, et al: Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene 18:1529-1535, 1999[CrossRef][Medline] 58. Ye Y, Vasavada S, Kuzmin I, et al: Subcellular localization of the von Hippel-Lindau disease gene product is cell cycle-dependent. Int J Cancer 78:62-69, 1998[Medline]
59. Lee S, Chen DY, Humphrey JS, et al: Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density. Proc Natl Acad Sci U S A 93:1770-1775, 1996
60. Lee S, Neumann M, Stearman R, et al: Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel-Lindau tumor suppressor protein. Mol Cell Biol 19:1486-1497, 1999
61. Duan DR, Humphrey JS, Chen DY, et al: Characterization of the VHL tumor suppressor gene product: Localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci U S A 92:6459-6463, 1995 62. Hergovich A, Lisztwan J, Barry R, et al: Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 5:64-70, 2003[CrossRef][Medline] 63. Bohling T, Hatva E, Kujala M, et al: Expression of growth factors and growth factor receptors in capillary hemangioblastoma. J Neuropathol Exp Neurol 55:522-527, 1996[Medline]
64. Flamme I, Krieg M, Plate KH: Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2alpha. Am J Pathol 153:25-29, 1998 65. Morii K, Tanaka R, Washiyama K, et al: Expression of vascular endothelial growth factor in capillary hemangioblastoma. Biochem Biophys Res Commun 194:749-755, 1993[CrossRef][Medline] 66. Stratmann R, Krieg M, Haas R, et al: Putative control of angiogenesis in hemangioblastomas by the von Hippel-Lindau tumor suppressor gene. J Neuropathol Exp Neurol 56:1242-1252, 1997[Medline]
67. Wizigmann-Voos S, Breier G, Risau W, et al: Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 55:1358-1364, 1995
68. Takahashi A, Sasaki H, Kim SJ, et al: Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 54:4233-4237, 1994 69. Brown LF, Berse B, Jackman RW, et al: Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 143:1255-1262, 1993[Abstract] 70. Burk JR, Lertora JJ, Martinez IR Jr, et al: Renal cell carcinoma with erythrocytosis and elevated erythropoietic stimulatory activity. South Med J 70:955-958, 1977[Medline]
71. Golde DW, Bersch N, Cline MJ: Polycythemia vera: Hormonal modulation of erythropoiesis in vitro. Blood 49:399-405, 1977
72. Wiesener MS, Eckardt KU: Erythropoietin, tumours and the von Hippel-Lindau gene: Towards identification of mechanisms and dysfunction of oxygen sensing. Nephrol Dial Transplant 17:356-359, 2002 73. Kawafuchi JI, Shirakura T, Azuma M, et al: Hematological study on a case with cerebellar hemangioblastoma associated with erythrocytosis, with special reference to a erythropoiesis-stimulating activity present in the fluid of the cyst of tumor. Blut 20:69-75, 1970[CrossRef][Medline] 74. Krieg M, Haas R, Brauch H, et al: Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19:5435-5543, 2000[CrossRef][Medline]
75. Siemeister G, Weindel K, Mohrs K, et al: Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 56:2299-2301, 1996
76. Gnarra JR, Zhou S, Merrill MJ, et al: Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci U S A 93:10589-10594, 1996
77. Iliopoulos O, Levy AP, Jiang C, et al: Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A 93:10595-10599, 1996
78. Kishida T, Stackhouse TM, Chen F, et al: Cellular proteins that bind the von Hippel-Lindau disease gene product: Mapping of binding domains and the effect of missense mutations. Cancer Res 55:4544-4548, 1995
79. Kibel A, Iliopoulos O, DeCaprio JA, et al: Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 269:1444-1446, 1995
80. Duan DR, Pause A, Burgess WH, et al: Inhibition of transcription elongation by the VHL tumor suppressor protein. Science 269:1402-1406, 1995
81. Pause A, Lee S, Worrell RA, et al: The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci U S A 94:2156-2161, 1997
82. Lonergan KM, Iliopoulos O, Ohh M, et al: 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 18:732-741, 1998
83. Kamura T, Conrad MN, Yan Q, et al: The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2. Genes Dev 13:2928-2933, 1999 84. Bai C, Sen P, Hofmann K, et al: SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86:263-274, 1996[CrossRef][Medline] 85. Deshaies RJ: SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol 15:435-467, 1999[CrossRef][Medline]
86. Stebbins CE, Kaelin WG Jr., Pavletich NP: Structure of the VHL-ElonginC-ElonginB complex: Implications for VHL tumor suppressor function. Science 284:455-461, 1999
87. Iwai K, Yamanaka K, Kamura T, et al: Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A 96:12436-12441, 1999
88. Lisztwan J, Imbert G, Wirbelauer C, et al: The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev 13:1822-1833, 1999 89. Semenza GL: HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 13:167-171, 2001[CrossRef][Medline] 90. Maxwell PH, Wiesener MS, Chang GW, et al: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271-275, 1999[CrossRef][Medline]
91. Kamura T, Sato S, Iwai K, et al: Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci U S A 97:10430-10435, 2000 92. Ohh M, Park CW, Ivan M, et al: Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423-427, 2000[CrossRef][Medline] 93. Tanimoto K, Makino Y, Pereira T, et al: Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. Embo J 19:4298-4309, 2000[CrossRef][Medline]
94. Cockman ME, Masson N, Mole DR, et al: Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275:25733-25741, 2000
95. Pugh CW, O'Rourke JF, Nagao M, et al: Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. J Biol Chem 272:11205-11214, 1997
96. Kallio PJ, Wilson WJ, O'Brien S, et al: Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem 274:6519-6525, 1999
97. Huang LE, Gu J, Schau M, et al: Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 95:7987-7992, 1998
98. Ivan M, Kondo K, Yang H, et al: HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science 292:464-468, 2001
99. Jaakkola P, Mole DR, Tian YM, et al: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468-472, 2001
100. Yu F, White SB, Zhao Q, et al: HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A 98:9630-9635, 2001 101. Masson N, Willam C, Maxwell PH, et al: Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. Embo J 20:5197-5206, 2001[CrossRef][Medline]
102. Maynard MA, Qi H, Chung J, et al: Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem 278:11032-11040, 2003
103. Min JH, Yang H, Ivan M, et al: Structure of an HIF-1alpha -pVHL complex: Hydroxyproline recognition in signaling. Science 296:1886-1889, 2002 104. Hon WC, Wilson MI, Harlos K, et al: Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 417:975-978, 2002[CrossRef][Medline] 105. Epstein AC, Gleadle JM, McNeill LA, et al: C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43-54, 2001[CrossRef][Medline]
106. Bruick RK, McKnight SL: A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337-1340, 2001
107. Ivan M, Haberberger T, Gervasi DC, et al: Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A 99:13459-13464, 2002 108. Taylor MS: Characterization and comparative analysis of the EGLN gene family. Gene 275:125-132, 2001[CrossRef][Medline] 109. Kallio PJ, Okamoto K, O'Brien S, et al: Signal transduction in hypoxic cells: Inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. Embo J 17:6573-6586, 1998[CrossRef][Medline] 110. Ema M, Hirota K, Mimura J, et al: Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: Their stabilization and redox signal-induced interaction with CBP/p300. Embo J 18:1905-1914, 1999[CrossRef][Medline]
111. Lando D, Peet DJ, Gorman JJ, et al: FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16:1466-1471, 2002
112. Lando D, Peet DJ, Whelan DA, et al: Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858-861, 2002
113. Mahon PC, Hirota K, Semenza GL: FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15:2675-2686, 2001
114. Sang N, Fang J, Srinivas V, et al: Carboxyl-terminal transactivation activity of hypoxia-inducible factor 1 alpha is governed by a von Hippel-Lindau protein-independent, hydroxylation-regulated association with p300/CBP. Mol Cell Biol 22:2984-2992, 2002 115. Eng C, Kiuru M, Fernandez MJ, et al: A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 3:193-202, 2003[CrossRef][Medline] 116. Arias-Sella Jav, J: Chief cell hyperplasia in the human carotid body at high altitudes: Physiologic and pathoogic significance. Hum Pathol 7:361-373, 1976[Medline]
117. Chandel NS, Schumacker PT: Cellular oxygen sensing by mitochondria: Old questions, new insight. J Appl Physiol 88:1880-1889, 2000 118. Aravind L, Koonin EV: The DNA-repair protein ALKLK, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases. Genome Biol 2:research0007.1-0007.8, 2001 119. Gimenez-Roqueplo AP, Favier J, Rustin P, et al: The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 69:1186-1197, 2001[CrossRef][Medline]
120. Gimenez-Roqueplo AP, Favier J, Rustin P, et al: Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 87:4771-4774, 2002
121. Hoffman MA, Ohh M, Yang H, et al: Von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10:1019-1027, 2001
122. Pastore YD, Jelinek J, Ang S, et al: Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood 101:1591-1595, 2003 123. Ang SO, Chen H, Hirota K, et al: Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32:614-621, 2002[CrossRef][Medline]
124. Elson DA, Thurston G, Huang LE, et al: Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha. Genes Dev 15:2520-2532, 2001 125. Rebar EJ, Huang Y, Hickey R, et al: Induction of angiogenesis in a mouse model using engineered transcription factors. Nat Med 8:1427-1432, 2002[CrossRef][Medline]
126. Vincent KA, Shyu KG, Luo Y, et al: Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor. Circulation 102:2255-2261, 2000
127. Jiang Y, Zhang W, Kondo K, et al: Gene Expression Profiling in a Renal Cell Carcinoma Cell Line: Dissecting VHL and Hypoxia-Dependent Pathways. Mol Cancer Res 1:453-462, 2003 128. Wykoff CC, Pugh CW, Maxwell PH, et al: Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene 19:6297-6305, 2000[CrossRef][Medline]
129. Okuda H, Saitoh K, Hirai S, et al: The von Hippel-Lindau tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C. J Biol Chem 276:43611-43617, 2001
130. Pal S, Claffey KP, Cohen HT, et al: Activation of Sp1-mediated vascular permeability factor/vascular endothelial growth factor transcription requires specific interaction with protein kinase C zeta. J Biol Chem 273:26277-26280, 1998 131. Okuda H, Hirai S, Takaki Y, et al: Direct interaction of the beta-domain of VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes. Biochem Biophys Res Commun 263:491-497, 1999[CrossRef][Medline]
132. Datta K, Nambudripad R, Pal S, et al: Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer. J Biol Chem 275:20700-20706, 2000 133. Li Z, Wang D, Na X, et al: Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor. Biochem Biophys Res Commun 294:700-709, 2002[CrossRef][Medline]
134. Li Z, Na X, Wang D, et al: Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein. J Biol Chem 277:4656-4662, 2002
135. Kuznetsova AV, Meller J, Schnell PO, et al: 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 U S A 100:2706-2711, 2003
136. Zhou MI, Wang H, Ross JJ, et al: The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J Biol Chem 277:39887-39898, 2002 137. Li Z, Wang D, Na X, et al: The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity. Embo J 22:1857-1867, 2003[CrossRef][Medline] 138. Ohh M, Yauch RL, Lonergan KM, et al: The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell 1:959-968, 1998[CrossRef][Medline]
139. Lieubeau-Teillet B, Rak J, Jothy S, et al: Von Hippel-Lindau gene-mediated growth suppression and induction of differentiation in renal cell carcinoma cells grown as multicellular tumor spheroids. Cancer Res 58:4957-4962, 1998
140. Esteban-Barragan MA, Avila P, Alvarez-Tejado M, et al: Role of the von Hippel-Lindau tumor suppressor gene in the formation of beta1-integrin fibrillar adhesions. Cancer Res 62:2929-2936, 2002
141. Koochekpour S, Jeffers M, Wang PH, et al: The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol 19:5902-5912, 1999
142. Davidowitz EJ, Schoenfeld AR, Burk RD: VHL induces renal cell differentiation and growth arrest through integration of cell-cell and cell-extracellular matrix signaling. Mol Cell Biol 21:865-874, 2001
143. Pause A, Lee S, Lonergan KM, et al: The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A 95:993-998, 1998
144. Bindra RS, Vasselli JR, Stearman R, et al: VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells. Cancer Res 62:3014-3019, 2002
145. Zatyka M, da Silva NF, Clifford SC, et al: Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Cancer Res 62:3803-3811, 2002
146. Gunaratnam L, Morley M, Franovic A, et al: HIF activates the TGF-alpha /EGF-R growth stimulatory pathway in VHL-/- renal cell carcinoma cells. J Biol Chem 278:44966-44974, 2003
147. de Paulsen N, Brychzy A, Fournier MC, et al: Role of transforming growth factor-alpha in von Hippel–Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci U S A 98:1387-1392, 2001
148. Knebelmann B, Ananth S, Cohen HT, et al: Transforming growth factor alpha is a target for the von Hippel-Lindau tumor suppressor. Cancer Res 58:226-231, 1998
149. Gnarra JR, Ward JM, Porter FD, et al: Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci U S A 94:9102-9107, 1997
150. Haase VH, Glickman JN, Socolovsky M, et al: Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A 98:1583-1588, 2001 151. Zagzag D, Zhong H, Scalzitti JM, et al: Expression of hypoxia-inducible factor 1alpha in brain tumors: Association with angiogenesis, invasion, and progression. Cancer 88:2606-2618, 2000[CrossRef][Medline] 152. Vortmeyer AO, Gnarra JR, Emmert-Buck MR, et al: Von Hippel-Lindau gene deletion detected in the stromal cell component of a cerebellar hemangioblastoma associated with von Hippel-Lindau disease. Hum Pathol 28:540-543, 1997[CrossRef][Medline] 153. Reifenberger G, Reifenberger J, Bilzer T, et al: Coexpression of transforming growth factor-alpha and epidermal growth factor receptor in capillary hemangioblastomas of the central nervous system. Am J Pathol 147:245-250, 1995[Abstract]
154. Benjamin LE, Keshet E: Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci U S A 94:8761-8766, 1997 155. Kondo K, Kim WY, Lechpammer M, et al: Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 1:E83, 2003
156. Zimmer M, Doucette D, Siddiqui N, et al: Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL–/– tumors. Mol Cancer Res 2:89-95, 2004 157. Drevs J, Medinger M, Schmidt-Gersbach C, et al: Receptor tyrosine kinases: The main targets for new anticancer therapy. Curr Drug Targets 4:113-121, 2003[CrossRef][Medline] 158. Aiello LP, George DJ, Cahill MT, et al: Rapid and durable recovery of visual function in a patient with von hippel-lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor su5416. Ophthalmology 109:1745-1751, 2002[CrossRef][Medline]
159. Richard S, Croisille L, Yvart J, et al: Paradoxical secondary polycythemia in von Hippel-Lindau patients treated with anti-vascular endothelial growth factor receptor therapy. Blood 99:3851-3853, 2002 160. Rogers LR, Kaelin W, Nadler P, et al: Response of cerebellar hemangioblastomas associated with von Hippel-Lindau disease to OSI-774 (TarcevaTM). Proc Am Soc Clin Oncol 21:75b, 2002 (abstr 2111) 161. Fabbro D, Garcia-Echeverria C: Targeting protein kinases in cancer therapy. Curr Opin Drug Discov Devel 5:701-712, 2002[Medline] 162. Mandriota SJ, Turner KJ, Davies DR, et al: HIF activation identifies early lesions in VHL kidneys: Evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1:459-468, 2002[CrossRef][Medline] 163. Lubensky IA, Gnarra JR, Bertheau P, et al: Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients. Am J Pathol 149:2089-2094, 1996[Abstract] 164. Zhuang Z, Roth MJ, Emmert-Buck MR, et al: Detection of the von Hippel-Lindau gene deletion in cytologic specimens using microdissection and the polymerase chain reaction. Acta Cytol 38:671-675, 1994[Medline] 165. Zhuang Z, Gnarra JR, Dudley CF, et al: Detection of von Hippel-Lindau disease gene mutations in paraffin-embedded sporadic renal cell carcinoma specimens. Mod Pathol 9:838-842, 1996[Medline]
166. Wiesener MS, Munchenhagen PM, Berger I, et al: Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas. Cancer Res 61:5215-5222, 2001
167. Mydlo JH, Michaeli J, Cordon-Cardo C, et al: Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue. Cancer Res 49:3407-3411, 1989 168. Kondo K, Klco J, Nakamura E, et al: Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1:237-246, 2002[CrossRef][Medline] 169. Maranchie JK, Vasselli JR, Riss J, et al: The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1:247-255, 2002[CrossRef][Medline]
170. Drevs J, Hofmann I, Hugenschmidt H, et al: Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res 60:4819-4824, 2000
171. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003
172. Clifford SC, Cockman ME, Smallwood AC, et al: Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet 10:1029-1038, 2001
173. Tian H, Hammer RE, Matsumoto AM, et al: The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 12:3320-3324, 1998 174. Schnell PO, Ignacak ML, Bauer AL, et al: Regulation of tyrosine hydroxylase promoter activity by the von Hippel-Lindau tumor suppressor protein and hypoxia-inducible transcription factors. J Neurochem 85:483-491, 2003[Medline]
175. Kroll SL, Paulding WR, Schnell PO, et al: Von Hippel-Lindau protein induces hypoxia-regulated arrest of tyrosine hydroxylase transcript elongation in pheochromocytoma cells. J Biol Chem 274:30109-30114, 1999
176. Bauer AL, Paulding WR, Striet JB, et al: Endogenous von Hippel-Lindau tumor suppressor protein regulates catecholaminergic phenotype in PC12 cells. Cancer Res 62:1682-1687, 2002 Submitted May 9, 2003; accepted September 1, 2004.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
VON HIPPEL-LINDAU DISEASE
