CG&D
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, H.
Right arrow Articles by Kaelin, W. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, H.
Right arrow Articles by Kaelin, W. G., Jr.
Cell Growth & Differentiation Vol. 12, 447-455, September 2001
© 2001 American Association for Cancer Research


Review

Molecular Pathogenesis of the Von Hippel-Lindau Hereditary Cancer Syndrome

Implications for Oxygen Sensing

Haifeng Yang and William G. Kaelin, Jr.1

Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School [H. Y., W. G. K.], and Howard Hughes Medical Institute [W. G. K.], Boston, Massachusetts 02115


    Background
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
The familial occurrence of blood vessel tumors of the retina, called retinal angiomas, was first described ~100 years ago by Treacher Collins and Eugene von Hippel (1 , 2) . Approximately 20 years later a Swedish neuropathologist, Arvind Lindau, described the association of these lesions with similar lesions of the brain and spinal cord, called hemangioblastomas (3) . Histopathologically, the retinal lesions and central nervous system lesions are identical. Hence, it has been suggested that they all be referred to as hemangioblastomas (4) . This disorder, which came to be known as VHL2 disease, is also associated with an increased risk of other tumors including clear cell carcinomas of the kidney, pheochromocytomas, islet cell tumors of the pancreas, endolymphatic sac tumors, and cystadenomas of the epididymis (men) and broad ligament (women). In addition, patients with VHL disease may develop cystic changes in a variety of viscera (notably the kidneys and pancreas) as well as lesions resembling the hemangioblastomas described above in the adrenal glands, lungs, and liver.


    Genetics of VHL Disease
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
VHL Disease affects ~1/35,000 individuals and is inherited in a seemingly autosomal dominant manner. In the 1980s investigators began linkage studies on VHL families and determined that the VHL gene resided on chromosome 3p25-, a region of the genome that had been shown earlier to be commonly deleted in renal cell carcinoma (5, 6, 7, 8, 9, 10) . Using this information, a consortium headed by Michael Lerman, Marston Linehan, and Bert Zbar at the National Cancer Institute and Eamonn Maher at Cambridge University in Cambridge, England, isolated the VHL gene in 1993 (11) . Essentially all of the individuals with a clinical diagnosis of VHL disease can be shown to harbor a germ-line mutation of the VHL gene (12) . In some families the relevant mutation is deletion of the entire VHL locus, which can be demonstrated by quantitative Southern blot analysis (12) . Some cases of apparently de novo VHL disease are linked to paternal or maternal mosaicism at the VHL locus (13 , 14) .

Individuals with VHL disease are germ-line heterozygotes at the VHL locus (that is, are VHL +/-). Using laser capture microdissection techniques, it has been shown that the hemangioblastomas and renal cysts that develop in these patients contain cells that are VHL -/- (15, 16, 17, 18, 19) . In other words, these tumors contain cells that have somatically lost the remaining wild-type VHL allele. Thus, at the molecular level, VHL disease is autosomal recessive and conforms to the so-called "Knudson Two-Hit Model" of carcinogenesis. Because the renal cysts in this disorder are VHL-/-, it is presumed that additional mutations are required for conversion from a benign renal cyst to a renal carcinoma. An analogous situation has been described in the colon where inactivation of the adenomatous polyposis coli (APC) gene gives rise to benign polyps, which, after additional mutations at other loci, can become colon carcinomas (20 , 21) . In keeping with the Knudson Two-Hit Model, biallelic VHL inactivation occurs commonly in sporadic hemangioblastoma and renal cell carcinomas (22, 23, 24, 25, 26, 27, 28, 29) . In this setting both "hits" occur somatically. The VHL gene is hypermethylated and, hence, transcriptionally silenced in some sporadic renal carcinomas that have not sustained VHL mutations (30 , 31) . There have been conflicting reports as to whether the spectrum of VHL mutations observed in VHL disease differs with respect to the mutations observed in sporadic tumors (25 , 32) . It is possible that some sporadic VHL mutations would not be tolerated in the germ line (e.g., if associated with certain "gain-of-function" effects) and that some sporadic VHL mutations are nonrandom because of exposure to specific environmental carcinogens. With respect to the later possibility, some somatic VHL mutations have been linked to exposure to organic solvents such as trichloroethylene (33) .

Restoration of VHL function in VHL -/- renal carcinoma cells suppresses their ability to form tumors in nude mice xenograft assays and, under certain conditions, their ability to proliferate in vitro (32 , 34, 35, 36, 37, 38, 39) . Thus, the VHL gene is a tumor suppressor gene by both genetic and functional criteria.


    Genotype-Phenotype Correlations
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
Genotype-phenotype correlations are emerging in VHL disease. VHL families can be subclassified based on whether they are at low risk (type 1) or high risk (type 2) of developing pheochromocytoma. Among those with type 2 disease are those with low (2A) or high (2B) risk of pheochromocytoma. Finally, some VHL families present as familial pheochromocytoma (2C) without the other classical stigmata of VHL disease. In general, type 2 families are more likely to have missense mutations than type 1 families (40) . This has led to the notion that either pheochromocytoma development is linked to a VHL "gain-of-function" or that the cells that give rise to pheochromocytoma cannot tolerate complete loss of VHL function. A challenge in the field is to determine how the loss (or gain) of specific VHL functions, as described below, affect the site-specific tumor risk in VHL disease.


    The VHL Gene
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
The VHL gene contains 3 exons and encodes an ~4.5 kb mRNA with an unusually long 3' untranslated region that contains multiple ALU repeats (41) . Alternative splicing gives rise to a second transcript in which exon 2 is not represented. This mRNA variant is presumed to be at least partially inactive with respect to VHL tumor suppression capability, because some kidney cancers produce this mRNA but not the exon 1–2-3 form (29) . The VHL promoter has been characterized and contains potential binding sites for a number of transcription factors including Sp1, PAX, and Nuclear Respiratory Factor 1 (42) . The VHL gene is ubiquitously expressed during development and in the adult (43, 44, 45, 46) . Thus, the pattern of VHL gene expression does not readily explain the restricted subset of tumors observed in VHL patients. Similar conundrums exist for other tumor suppressor genes (e.g., the retinoblastoma gene).


    The pVHL
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
The VHL mRNA encodes a protein that contains 213 amino acid residues with an apparent molecular weight of Mr 24,000–30,000 based on electrophoretic mobility (34) . A second protein isoform with an apparent molecular weight of Mr 18,000–20,000 is produced as a result of internal translation initiation using an ATG at codon 54 (47, 48, 49) . In some cells this is the major pVHL isoform. Why cells produce two different pVHL products is not clear, because the two proteins behave similarly in most of the biochemical and functional assays described to date. For this reason, the term "pVHL" is often used when generically describing the two VHL proteins. The predicted primary sequence of pVHL is not highly similar to other known proteins and, hence, did not provide any immediate clues as to its probable functions.

pVHL resides primarily in the cytoplasm, but a significant fraction can also be found in the nucleus or associated with cell membranes (34 , 43 , 50, 51, 52, 53, 54, 55) . Importantly, pVHL function has been linked to its ability to shuttle between the cytoplasm and nucleus. Shuttling by pVHL requires ongoing RNA transcription, because treatment of cells with inhibitors of RNA polymerase leads to nuclear accumulation of pVHL (53) . Recent studies indicate that shuttling by pVHL is both Ran and energy-dependent and requires sequences encoded by VHL exon 2 (56 , 57) . It is currently believed that shuttling by pVHL is linked to its ability to act as a ubiquitin ligase, as described below.


    pVHL Regulates Hypoxia-inducible Genes
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
The tumors that have been linked to VHL inactivation share several properties. First, they are typically highly vascular and overproduce angiogenic peptides such as VEGF (58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68) . Second, they can occasionally overproduce the hormone erythropoietin, which causes striking increases in RBC production leading to polycythemia (69) . As both VEGF and erythropoietin are normally induced by hypoxia, this led to the hypothesis that pVHL was involved in cellular adaptation to changes in oxygen. Indeed, several groups went on to show that cells lacking pVHL constitutively overproduce hypoxia-inducible mRNAs and that restoration of pVHL function in such cells led to suppression of hypoxia-inducible mRNAs in the presence of oxygen (39 , 63 , 64 , 70, 71, 72, 73) . In other words, continued accumulation of hypoxia-inducible mRNAs in the presence of oxygen is a molecular signature of pVHL-inactivation.


    The pVHL/Elongin B and C/Cul2 Complex
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
To understand how pVHL functions biochemically, investigators sought to identify pVHL-interacting proteins. It is now clear that pVHL forms stable, multimeric complexes that contain Elongin B, Elongin C, Cul2, and Rbx1 (74, 75, 76, 77, 78, 79, 80) . Elongin B and C were first identified as components of a transcriptional elongation complex called Elongin/SIII, which also contained Elongin A (81) . This, coupled with in vitro biochemical studies, led to earlier speculation that pVHL might regulate transcription by competing with Elongin A for binding to Elongins B and C (74) . Whereas not formally disproven, it was subsequently shown that Elongin B and C are in vast molar excess of both pVHL and Elongin A and that Elongin B and C probably perform multiple functions in the cell (82) . A major insight was provided by Bai et al. (83) who noted that Elongin C resembled a yeast protein called Skp1. This, coupled with the knowledge that Cul2 was a member of a protein family (Cullins; Ref. 84 ) that resembled the yeast protein Cdc53 (85 , 86) , led to the idea that the pVHL/Elongin/Cul2 complex might function similarly to so-called Skp1/Cdc53/F-Box protein complexes in yeast. The regulated destruction of many proteins is accomplished by covalent linkage to polyubiquitin chains, which serve as signals for degradation by the 26S proteasome. Polyubiquitination requires the action of an E1 ubiquitin activating enzyme, an E2 ubiquitin conjugating enzyme, and often an E3 ubiquitin ligase. Skp1/Cdc53/F-Box protein complexes act as E3 ligases with the F-box protein (so named because of a colinear motif first identified in cyclin F) serving as the substrate recognition module (83 , 87) . Accordingly, it was hypothesized that the pVHL complex was a ubiquitin ligase and that pVHL itself would bind to the putative ubiquitination target.

The notion that the pVHL/Elongin/Cul2 complex was a ubiquitin ligase was strengthened by two separate lines of investigation. First, the crystal structure of pVHL bound to Elongin B and C showed that the region of pVHL that binds to Elongin C (now called the {alpha} domain) loosely resembles an F-box and that Elongin C does, indeed, resemble Skp1 (88) . Importantly, the structure also revealed that the mutations described in VHL disease clustered in two subdomains, namely, the above-mentioned {alpha} domain and a second region, called the ß domain, which had the properties of a substrate-binding site. Second, two groups showed that anti-pVHL immunopreciptiates contained ubiquitin ligase activity, indicating that pVHL was, or was tightly associated with, a ubiquitin ligase (89 , 90) .


    pVHL Polyubiquitinates HIF
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
Maxwell et al. (73) examined the status of the HIF transcription factor in pVHL-defective cells in light of the above-mentioned finding that such cells frequently overproduce hypoxia-inducible mRNAs. HIF is a heterodimeric, sequence-specific, DNA-binding transcriptional activator made up of an {alpha} subunit (such as HIF1{alpha} or HIF2{alpha}) and a ß subunit (such as HIF1ß, which is also called ARNT; Refs. 91, 92, 93 ). Earlier studies showed that HIF{alpha} subunits are rapidly degraded in the presence of oxygen, whereas the ß subunits are constitutively present. Maxwell et al. (73) showed that pVHL-defective cells are apparently unable to degrade HIF{alpha} subunits and, furthermore, that pVHL and HIF{alpha} subunits can physically associate.

Subsequently, several groups showed that pVHL binds directly to a region of HIF called the oxygen-dependent degradation domain, which was shown earlier to render HIF unstable in the presence of oxygen and directs the polyubiquitination of HIF (94, 95, 96, 97) . Furthermore, binding to HIF is mediated by the pVHL ß domain, thus confirming the earlier prediction that the pVHL ß domain might serve as a substrate docking site. All of the pVHL mutants associated with the classical stigmata of VHL disease tested to date are defective with respect to HIF polyubiquitination activity, either because they cannot bind to HIF (such as after mutation of the ß domain), cannot engage the Elongin C/Cul2-containing complex (such as after mutation of the {alpha} domain), or both (such as after mutations that alter the overall confirmation of pVHL; Refs. 94 , 96 , 98, 99, 100 ). In summary, regulation of HIF turnover provided the link between pVHL polyubiquitination activity and the regulation of hypoxia-inducible mRNAs.


    An Oxygen-dependent Post-translational Modification Governs the Interaction betweenpVHL and HIF
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
These studies left open the question of how HIF polyubiquitination is prevented under hypoxic conditions. To address this question, two groups independently showed that the interaction of pVHL with HIF required that HIF first undergo a post-translational modification (101 , 102) . They then mapped the pVHL binding site in HIF to a short peptidic determinant contained within the oxygen-dependent degradation domain. Interestingly, an earlier study by Srinivas et al. (103) had noted a highly conserved 8 amino acid residue sequence within this peptide which, when converted to 8 alanines, led to HIF stabilization. Using a variety of techniques including site-directed mutagenesis and mass spectrometry analysis, it was determined that the relevant modification of HIF was enzymatic hydroxylation of proline 564 located within the core of the above-mentioned 8mer peptide (101 , 102 ; Fig. 1Citation ). This reaction requires the presence of oxygen and iron and, thus, provides a mechanistic link between oxygen availability and HIF recognition by pVHL. Furthermore, it explains the observation that iron chelators, as well as transition metals such as CoCl2, can act as hypoxia-mimetics and stabilize HIF.



View larger version (23K):
[in this window]
[in a new window]
 
Fig. 1. Oxygen-dependent polyubiquitination of HIF by pVHL. The {alpha} subunits of the heterodimeric transcription factor HIF contain a conserved proline residue (P) that becomes hydroxylated in the presence of oxygen. This serves as a signal for binding to the pVHL, which is a component of an E3 ubiquitin ligase containing elongin B (B), elongin C (C), Cul2, Rbx1, and an as yet identified ubiquitin conjugating enzyme (E2?).

 
The well-studied prolyl hydroxylases modify collagen and a handful of other proteins that share sequences that are similar to the canonical prolyl hydroxylation sites present in collagen (104 , 105) . These enzymes are unlikely to modify HIF, because they are located in the endoplasmic reticulum, and because the residues flanking the HIF proline site do not resemble the sequences found in their known substrates. In short, it is likely that HIF is modified by a novel prolyl hydroxylase. How mammalian cells sense changes in oxygen availability is an important question in biology. The HIF prolyl hydroxylase may be a critical component of the mammalian oxygen sensing apparatus. It will also be important to ask whether other cellular proteins are likewise subject to prolyl hydroxylation.


    Control of Extracelluar Matrix by pVHL
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
pVHL almost certainly has functions in addition to regulation of HIF. pVHL binds directly to fibronectin, and this interaction is abrogated by all of the naturally occurring VHL mutations examined to date (100 , 106) . Cells lacking functional pVHL, including mouse embryo fibroblasts engineered to be VHL -/-, fail to produce a recognizable extracellular fibronectin matrix (106) . In the case of renal carcinoma cells, this defect can be corrected by stable transfection with a plasmid encoding wild-type pVHL. How and why the interaction of pVHL with fibronectin affects extracellular fibronectin matrix assembly is not known. It remains possible that pVHL affects the processing or turnover of specific forms of fibronectin, but this remains to be proven. A role of pVHL in extracellular matrix formation is also suggested by the finding that pVHL down-regulates the production of certain tissue inhibitor of metalloproteinases whereas it up-regulates the production of certain matrix metalloproteinases (107) . Moreover, differences in the cellular morphology and growth characteristics of wild-type and pVHL-defective cells in vitro can be unmasked by plating on different extracellular matrices (37) .

As described above, some VHL mutations are associated with familial pheochromocytoma without the other classical stigmata of VHL disease. Two groups showed that such mutants retained the ability to regulate HIF but displayed defects with respect to promotion of fibronectin matrix assembly (99 , 100) . This suggests that altered fibronectin assembly is linked to pheochromocytoma development, whereas regulation of HIF may be sufficient to suppress hemangioblastoma and renal carcinoma development. Of course, in analyses of this type it remains possible that fibronectin-binding and HIF-binding are surrogates for as yet unknown functions of pVHL, which are similarly affected by such mutations.


    Control of Cell-Cycle by pVHL
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
Cells lacking wild-type pVHL display defects in cell-cycle exit under certain experimental conditions (37 , 108) . Whether the effect of pVHL on cell-cycle control relates to its ability to regulate HIF, extracellular matrix, both, or neither, is not known. It is possible, for example, that the control of the cell-cycle by pVHL reflects its ability to regulate HIF target genes, which encode certain mitogens. In this regard, the epithelial mitogen TGF-{alpha} is up-regulated in pVHL-defective cells and is the product of a HIF-target gene (109 , 110) . de Paulsen et al. (109) showed that renal epithelial are particularly sensitive to the mitogenic effects of TGF-{alpha}, perhaps contributing to the observed tissue specificity of pVHL-associated neoplasia. Interestingly, earlier studies showed that TGF-{alpha} and its receptor, epidermal growth factor receptor, are frequently up-regulated in hemangioblastoma and renal cell carcinoma (59 , 111, 112, 113, 114, 115, 116) .


    Animal Models of VHL Disease
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
VHL orthologues have been identified in mice, rat, flies, and worms (51 , 117, 118, 119, 120) . In the fly, VHL inactivation causes abnormalities in tracheal development consistent with a role of VHL in oxygen sensing (117) . In the mouse, VHL -/- embryos are not viable and exhibit profound defects in placental development (121) . This observation may relate to the important role of HIF in governing the behavior of trophoblasts during uterine invasion and placental development (122, 123, 124) . Interestingly, trophoblast pVHL undergoes highly choreographed changes in abundance and subcellular localization during this process in normal cells (125) . An earlier report found no abnormalities in VHL +/- (121) . However, a second group subsequently reported the development of highly vascular tumors, reminiscent of hemangioblastomas, arising in independently generated VHL +/- mice (126) . Similar lesions were observed after conditional inactivation of VHL in mouse livers using Cre recombinase under the control of the albumin promoter (126) . These tumors were found to overproduce HIF and its target genes.


    Pathogenesis of VHL-associated Neoplasms
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
A central question is why loss of pVHL gives rise to tumor formation. With respect to hemangioblastoma formation, laser capture studies in situ and immunohistochemical studies suggest that it is a poorly understood "stromal" cell of uncertain embryological origin, which has lost the function of pVHL and overproducing hypoxia-inducible mRNAs (Refs. 16 , 19 , 39 , 60 , 127 , 128 ; Fig. 2Citation ). Some of these mRNAs, such as the VEGF mRNA and PDGF mRNA, encode proteins that are likely to act in a paracrine fashion to stimulate the growth and survival of endothelial cells and pericytes, respectively. In this regard, forced expression of VEGF in the brain can induce the formation of immature blood vessels (58) . Other mRNAs, such as the TGF-{alpha} mRNA, encode proteins that are likely to act in an autocrine fashion to stimulate the stromal cells. If this model is correct, blockade of VEGF and TGF-{alpha} signaling through their receptors, kinase insert domain receptor and epidermal growth factor receptor, respectively, might be therapeutic.



View larger version (60K):
[in this window]
[in a new window]
 
Fig. 2. Pathogenesis of hemangioblastoma in VHL disease. A poorly understood stromal cell undergoes loss of the remaining wild-type VHL allele, leading to loss of pVHL function and consequent overproduction of mRNAs encoded by hypoxia-inducible genes. Some of these mRNAs encode angiogenic peptides, such as PDGF and VEGF, whereas others encode autocrine growth factors such as TGF-{alpha}.

 
As described above, loss of pVHL function in the kidney is only sufficient to cause renal cysts. Renal cysts are usually the result of abnormal epithelial proliferation, abnormal epithelial cell-matrix interactions, or both (129, 130, 131) . Therefore, renal cyst formation after pVHL inactivation might relate to its antimitogenic effects as well as to its effects on extracellular matrix formation and turnover. Whereas additional mutations may be required for conversion of a benign cyst to a renal carcinoma in this setting, it is nonetheless likely that pVHL loss and consequent deregulation of HIF target genes contribute to the biological attributes of kidney cancer including their propensity to induce new blood vessels and to induce secondary polycythemia. It will be important to determine whether down-regulation of HIF is necessary and/or sufficient for pVHL to suppress tumor growth.

Finally, the role of pVHL in pheochromocytoma is particularly enigmatic. In contrast to hemangioblastoma and renal cell carcinoma, VHL mutations are rare in sporadic pheochromocytoma (29 , 132) . This is despite the fact that germ-line VHL mutations can cause pheochromocytoma. It is possible that pheochromocytoma development in the setting of VHL disease requires inactivation of VHL during a critical developmental window and/or is related to a VHL +/- "field defect" in the adrenal gland. As described above, pVHL mutants associated with "pheochromocytoma-only" VHL disease retain the ability to regulate HIF, suggesting that some other pVHL function, such as regulation of fibronectin matrix assembly, is linked to suppression of pheochromocytoma development.


    Summary
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 
Inactivation of the VHL tumor suppressor gene has been linked to the development of a variety of tumors including hemangioblastomas of the retina and central nervous system, clear cell carcinoma of the kidney, and pheochromocytoma. The pVHL gene product, pVHL, targets the HIF transcription factor for polyubiquitination and, hence, destruction in the presence of oxygen. The interaction of pVHL with HIF is governed by enzymatic hydroxylation of a conserved proline residue in HIF by an as yet unidentified prolyl hydroxylase. Loss of pVHL function leads to overexpression of mRNAs encoded by HIF target genes, such as VEGF, PDGF chain, and TGF-{alpha}, implicated in the development of VHL-associated neoplasms. Other functions of pVHL, which may or may not relate to its ability to regulate HIF, involve regulation of cell cycle exit and extracellular matrix formation.


    Acknowledgments
 
We apologize to colleagues whose work may not have been cited because of space limitations or oversight. Please bring egregious omissions to our attention at: william_kaelin{at}dfci.harvard.edu.


    Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should addressed, at Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Mayer Building Room 457, Boston MA 02115. Phone: (617) 632-3975; Fax: (617) 632-3975; E-mail: william_kaelin{at}dfci.harvard.edu Back

2 The abbreviations used are: VHL, von Hippel-Lindau; pVHL, VHL protein; VEGF, vascular endothelial growth factor; HIF, hypoxia-inducible factor; TGF, transforming growth factor; PDGF, platelet-derived growth factor. Back

Received for publication 7/30/01. Accepted for publication 8/ 2/01.


    References
 TOP
 Background
 Genetics of VHL Disease
 Genotype-Phenotype Correlations
 The VHL Gene
 The pVHL
 pVHL Regulates Hypoxia-inducible...
 The pVHL/Elongin B and...
 pVHL Polyubiquitinates HIF
 An Oxygen-dependent Post...
 Control of Extracelluar Matrix...
 Control of Cell-Cycle by...
 Animal Models of VHL...
 Pathogenesis of VHL-associated...
 Summary
 References
 

  1. Collins E. T. Intra-ocular growths (two cases, brother and sister, with peculiar vascular new growth, probably retinal, affecting both eyes). Trans. Ophthal. Soc. U. K., 14: 141-149, 1894.
  2. von Hippel E. Ueber eine sehr seltene Erkrankung der Nethaut. Graefe Arch Ophthal., 59: 83-106, 1904.
  3. Lindau A. Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation. Acta Opthal., 4: 193-226, 1927.
  4. Richard S., Campello C., Taillandier L., Parker F., Resche F. Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. J. Intern. Med., 243: 547-553, 1998.[Medline]
  5. Vance J., Small K., Jones M., Stajich J., Yamaoka L., Roses A., Hung W., Pericak-Vance M. Confirmation of linkage in von Hippel-Lindau disease. Genomics, 6: 565-567, 1990.[Medline]
  6. Crossey P., Maher E., Jones M., Richards F., Latif F., Phipps M., Lush M., Foster K., Tory K., Green J., Oostra B., Yates J., Linehan W., Affara N., Lerman M., Zbar B., Nakamura Y., Ferguson-Smith M. Genetic linkage between von Hippel-Lindau disease and three microsatellite polymorphisms refines the localization of the VHL locus. Hum. Mol. Genet., 2: 279-282, 1993.[Abstract/Free Full Text]
  7. Kalman T., Brauch H., Linehan M., Barba D., Oldfield E., Filling-Katz M., Seizinger B., Nakamura Y., White R., Marshall F. F., Lerman M. I., Zbar B. Specific genetic change in tumors associated with von-hippel-lindau disease. J. Natl. Cancer Inst., 81: 1097-1101, 1989.[Abstract/Free Full Text]
  8. Seizinger B. R., Rouleau G. A., Ozelius L. J., Lane A. H., Farmer G. E., Lamiell J. M., Haines J., Yuen J. W. M., Collins D., Majoor-Krakauer D., Bonner T., Mathew C., Rubenstein A., Halperin J., McConkie-Rosell A., Green J. S., Trofatter J. A., Ponder B. A., Eierman L., Bowmer M. I., Schimke R., Oostra B., Aronin N., Smith D. I., Drabkin H., Waziri M. H., Hobbs W. J., Martuza R. L., Conneally P. M., Hsia Y. E., Gusella J. F. Von-hippel lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature (Lond.), 332: 268-269, 1988.[Medline]
  9. Tory K., Brauch H., Linehan M., Barba D., Oldfield E., Filling-Katz M., Seizinger B., Nakamura Y., White R., Marshall F. Specific genetic change in tumors associated with von Hippel-Lindau disease. J. Natl. Cancer Inst., 81: 1097-1101, 1989.
  10. Maher E., Bentley E., Yates J., Latif F., Lerman M., Zbar B., Affara N., Ferguson-Smith M. Localization of the gene for von Hippel-lindau disease to a small region of chromosome 3p by genetic linkage analysis. Genomics, 10: 957-960, 1991.[Medline]
  11. Latif F., Tory K., Gnarra J., Yao M., Duh F-M., Orcutt M. L., Stackhouse T., Kuzmin I., Modi W., Geil L., Schmidt L., Zhou F., Li H., Wei M. H., Chen F., Glenn G., Choyke P., Walther M. M., Weng Y., Duan D-S. R., Dean M., Glavac D., Richards F. M., Crossey P. A., Ferguson-Smith M. A., Pasiler D. L., Chumakov I., Cohen D., Chinault A. C., Maher E. R., Linehan W. M., Zbar B., Lerman M. I. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science (Wash. DC), 260: 1317-1320, 1993.[Abstract/Free Full Text]
  12. Stolle C., Glenn G., Zbar B., Humphrey J., Choyke P., Walther M., Pack S., Hurley K., Andrey C., Klausner R., Linehan W. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum. Mutat., 12: 417-423, 1998.[Medline]
  13. Murgia A., Martella M., Vinanzi C., Polli R., Perilongo G., Opocher G. Somatic mosaicism in von Hippel-Lindau disease. Hum. Mutat., 15: 114 2000.
  14. Sgambati M., Stolle C., Choyke P., Walther M., Zbar B., Linehan W., Glenn G. Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am. J. Hum. Genet., 66: 84-91, 2000.[Medline]
  15. Lubensky I. A., Gnarra J. R., Bertheau P., Walther M. M., Linehan W. M., Zhuang Z. 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.[Medline]
  16. Vortmeyer A., Gnarra J., Emmert-Buck M., Katz D., Linehan W., Oldfield E., Zhuang Z. 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.[Medline]
  17. Zhuang Z., Bertheau P., Emmert-Buck M., Liotta L., Gnarra J., Linehan W., Lubensky I. A microscopic dissection technique for archival DNA analysis of specific cell populations in lesions < 1mm in size. Am. J. Pathol., 146: 620-625, 1995.[Medline]
  18. Zhuang Z., Gnarra J. R., Dudley C. F., Zbar B., Linehan W. M., Lubensky I. A. Detection of von Hippel-Lindau disease gene mutations in paraffin-embedded sporadic renal cell carcinoma specimens. Mod. Pathol., 9: 838-842, 1996.[Medline]
  19. Chan C., Vortmeyer A., Chew E., Green W., Matteson D., Shen D., Linehan W., Lubensky I., Zhuang Z. VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. Arch. Ophthalmol., 117: 625-630, 1999.[Medline]
  20. Kinzler K., Vogelstein B. Lessons from hereditary colorectal cancer. Cell, 87: 159-170, 1996.[Medline]
  21. Kinzler K., Vogelstein B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature (Lond.), 386: 761-763, 1997.[Medline]
  22. Shuin T., Kondo K., Ashida S., Okuda H., Yoshida M., Kanno H., Yao M. Germline and somatic mutations in von Hippel-Lindau disease gene and its significance in the development of kidney cancer. Contrib. Nephrol., 128: 1-10, 1999.[Medline]
  23. Shuin T., Kondo K., Torigoe S., Kishida T., Kubota Y., Hosaka M., Nagashima Y., Kitamura H., Latif F., Zbar B., Lerman M. I., Yao M. 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.[Abstract/Free Full Text]
  24. Foster K., Prowse A., van den Berg A., Fleming S., Hulsbeek M. M. F., Crossey P. A., Richards F. M., Cairns P., Affara N. A., Ferguson-Smith M. A., Buys C. H. C. M., Maher E. R. Somatic mutations of the von Hippel-Lindau disease tumor suppressor gene in non-familial clear cell renal carcinoma. Hum. Mol. Genet., 3: 2169-2173, 1994.[Abstract/Free Full Text]
  25. Whaley J. M., Naglich J., Gelbert L., Hsia Y. E., Lamiell J. M., Green J. S., Collins D., Neumann H. P. H., Laidlaw J., Li F. P., Klein-Szanto A. J. P., Seizinger B. R., Kley N. Germ-Line mutations in the von Hippel-Lindau tumor suppressor gene are similar to somatic von Hippel-Lindau abberations in sporadic renal cell carcinoma. Am. J. Hum. Genet., 55: 1092-1102, 1994.[Medline]
  26. Clifford S., Prowse A., Affara N., Buys C., Maher E. 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.[Medline]
  27. Kanno H., Kondo K., Ito S., Yamamoto I., Fujii S., Torigoe S., Sakai N., Hosaka M., Shuin T., Yao M. Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous systems hemangioblastomas. Cancer Res., 54: 4845-4847, 1994.[Abstract/Free Full Text]
  28. Tse J., Wong J., Lo K-W., Poon W-S., Huang D., Ng H-K. 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]
  29. Gnarra J. R., Tory K., Weng Y., Schmidt L., Wei M. H., Li H., Latif F., Liu S., Chen F., Duh F-M., Lubensky I., Duan D. R., Florence C., Pozzatti R., Walther M. M., Bander N. H., Grossman H. B., Brauch H., Pomer S., Brooks J. D., Isaacs W. B., Lerman M. I., Zbar B., Linehan W. M. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat. Genet., 7: 85-90, 1994.[Medline]
  30. Herman J. G., Latif F., Weng Y., Lerman M. I., Zbar B., Liu S., Samid D., Duan D-S. R., Gnarra J. R., Linhean W. M., Baylin S. B. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl. Acad. Sci. (USA), 91: 9700-9704, 1994.[Abstract/Free Full Text]
  31. Brauch H., Weirich G., Brieger J., Glavac D., Rodl H., Eichinger M., Feurer M., Weidt E., Puranakanitstha C., Neuhaus C., Pomer S., Brenner W., Schirmacher P., Storkel S., Rotter M., Masera A., Gugeler N., Decker H. 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.[Abstract/Free Full Text]
  32. Gnarra J. R., Duan D. R., Weng Y., Humphrey J. S., Chen D. Y. T., Lee S., Pause A., Dudley C. F., Latif F., Kuzmin I., Schmidt L., Duh F-M., Stackhouse T., Chen F., Kishida T., Wei M. H., Lerman M. I., Zbar B., Klausner R. D., Linehan W. M. Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal cell carcinoma (Review). Biochim. Biophys. Acta, 1242: 201-210, 1996.[Medline]
  33. Brauch H., Weirich G., Hornauer M., Storkel S., Wohl T., Bruning T. Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. J. Natl. Cancer Inst., 91: 854-861, 1999.[Abstract/Free Full Text]
  34. Iliopoulos O., Kibel A., Gray S., Kaelin W. G. Tumor suppression by the human von Hippel-Lindau gene product. Nat. Med., 1: 822-826, 1995.[Medline]
  35. Chen F., Kishida T., Duh F-M., Renbaum P., Orcutt M. L., Schmidt L., Zbar B. Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. Cancer Res., 55: 4804-4807, 1995.[Abstract/Free Full Text]
  36. Pause A., Lee S., Lonergan K. M., Klausner R. D. The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc. Natl. Acad. Sci. (USA), 95: 993-998, 1998.[Abstract/Free Full Text]
  37. Davidowitz E., Schoenfeld A., Burk R. 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.[Abstract/Free Full Text]
  38. Kim M., Katayose Y., Li Q., Rakkar A., Li Z., Hwang S., Katayose D., Trepel J., Cowan K., Seth P. Recombinant adenovirus expressing Von Hippel-Lindau-mediated cell cycle arrest is associated with the induction of cyclin-dependent kinase inhibitor p27Kip1. Biochem. Biophys. Res. Commun., 253: 672-677, 1998.[Medline]
  39. Krieg M., Haas R., Brauch H., Acker T., Flamme I., Plate K. Up-regulation of hypoxia-inducible factors HIF-1{alpha} and HIF-2{alpha} under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene, 19: 5435-5443, 2000.[Medline]
  40. Zbar B., Kishida T., Chen F., Schmidt L., Maher E. R., Richards F. M., Crossey P. A., Webster A. R., Affara N. A., Ferguson-Smith M. A., Brauch H., Glavac D., Neumann H. P. H., Tisherman S., Mulvihill J. J., Gross D., Shuin T., Whaley J., Seizinger B., Kley N., Olschwang S., Boisson C., Richard S., Lips C. H. M., Linehan M. W., Lerman M. Germline mutations in the von Hippel-Lindau (VHL) gene in families from North America, Europe, and Japan. Hum. Mutat., 8: 348-357, 1996.[Medline]
  41. Renbaum P., Duh F-M., Latif F., Zbar B., Lerman M., Kuzmin I. 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.[Medline]
  42. Kuzmin I., Duh F-M., Latif F., Geil L., Zbar B., Lerman M. I. Identification of the promoter of the human von Hippel-Lindau disease tumor suppressor gene. Oncogene, 10: 2185-2194, 1995.[Medline]
  43. Los M., Jansen G. H., Kaelin W. G., Lips C. J. M., Blijham G. H., Voest E. E. Expression pattern of the von Hippel-Lindau protein in human tissues. Lab. Investig., 75: 231-238, 1996.[Medline]
  44. Nagashima Y., Miyagi Y., Udagawa K., Taki A., Misugi K., Sakai N., Kondo K., Kaneko S., Yao M., Shuin T. Von Hippel-Lindau tumor suppressor gene. Localization of expression by in situ hybridization. J. Pathol., 180: 271-274, 1996.[Medline]
  45. Richards F., Schofield P., Fleming S., Maher E. Expression of the von Hippel-Lindau disease tumor suppressor gene during human embryogenesis. Hum. Mol. Genet., 5: 639-644, 1996.[Abstract/Free Full Text]
  46. Kessler P., Vasavada S., Rackley R., Stackhouse T., Duh F., Latif F., Lerman M., Zbar B., Williams B. Expression of the von Hippel-Lindau tumor-suppressor gene, VHL, in human fetal kidney and during mouse embryogenesis. Mol. Med., 1: 457-466, 1995.[Medline]
  47. Iliopoulos O., Ohh M., Kaelin W. pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc. Natl. Acad. Sci. USA, 95: 11661-11666, 1998.[Abstract/Free Full Text]
  48. Blankenship C., Naglich J., Whaley J., Seizinger B., Kley N. Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene, 18: 1529-1535, 1999.[Medline]
  49. Schoenfeld A., Davidowitz E., Burk R. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc. Natl. Acad. Sci. USA, 1: 8817-8822, 1998.
  50. Corless C. L., Kibel A., Iliopoulos O., Kaelin W. G. J. Immunostaining of the von Hippel-Lindau gene product (pVHL) in normal and neoplastic human tissues. Hum. Pathol., 28: 459-464, 1997.[Medline]
  51. Duan D. R., Humphrey J. S., Chen D. Y. T., Weng Y., Sukegawa J., Lee S., Gnarra J. R., Linehan W. M., Klausner R. D. Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. Proc. Natl. Acad. Sci. USA, 92: 6495-6499, 1995.
  52. Lee S., Chen D. Y. T., Humphrey J. S., Gnarra J. R., Linehan W. M., Klausner R. D. Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density. Proc. Natl. Acad. Sci. USA, 93: 1770-1775, 1996.[Abstract/Free Full Text]
  53. Lee S., Neumann M., Stearman R., Stauber R., Pause A., Pavlakis G., Klausner R. 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.[Abstract/Free Full Text]
  54. Schoenfeld A., Davidowitz E., Burk R. Endoplasmic reticulum/cytosolic localization of von Hippel-Lindau gene products is mediated by a 64-amino acid region. Int. J. Cancer, 91: 457-467, 2001.[Medline]
  55. Ye Y., Vasavada S., Kuzmin I., Stackhouse T., Zbar B., Williams B. Subcellular localization of the von Hippel-Lindau disease gene product is cell cycle-dependent. Int. J. Cancer, 78: 62-69, 1998.[Medline]
  56. Groulx I., Bonicalzi M., Lee S. Ran-mediated nuclear export of the von Hippel-Lindau tumor suppressor protein occurs independently of its assembly with cullin-2. J. Biol. Chem., 275: 8991-9000, 2000.[Abstract/Free Full Text]
  57. Bonicalzi M., Groulx I., de Paulsen N., Lee S. Role of exon 2-encoded ß-domain of the von Hippel-Lindau tumor suppressor protein. J. Biol. Chem., 12: 1407-1416, 2001.
  58. Benjamin L. E., 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. USA, 94: 8761-8766, 1997.[Abstract/Free Full Text]
  59. Bohling T., Hatva E., Kujala M., Claesson-Welsh L., Alitalo K., Haltia M. Expression of growth factors and growth factor receptors in capillary hemangioblastoma. J. Neuropathol. Exp. Neurol., 55: 522-527, 1996.[Medline]
  60. Flamme I., Krieg M., Plate K. Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2{alpha}. Am. J. Pathol., 153: 25-29, 1998.[Medline]
  61. Grossniklaus H., Thomas J., Vigneswaran N., Jarrett W., III Retinal hemangioblastoma. A histologic, immunohistochemical, and ultrastructural evaluation. Ophthalmology, 99: 140-145, 1992.[Medline]
  62. Morii K., Tanaka R., Washiyama K., Kumanishi T., Kuwano R. Expression of vascular endothelial growth factor in capillary hemangioblastoma. Biochem. Biophys. Res. Commun., 194: 749-755, 1993.[Medline]
  63. Stratmann R., Krieg M., Haas R., Plate K. Putative control of angiogenesis in hemangioblastomas by the von Hippel-Lindau tumor suppressor gene. J. Neuropathol. Exp. Neurol., 56: 1242-1252, 1997.[Medline]
  64. Wizigmann-Voos S., Breier G., Risau W., Plate K. 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.[Abstract/Free Full Text]
  65. Takahashi A., Sasaki H., Kim S., Tobisu K., Kakizoe T., Tsukamoto T., Kumamoto Y., Sugimura T., Terada M. 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.[Abstract/Free Full Text]
  66. Berse B., Brown L., Livingston V., Dvorak H., Senger D. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol. Biol. Cell, 3: 211-220, 1992.[Abstract/Free Full Text]
  67. Brown L., Berse B., Jackman R., Tognazzi K., Manseau E., Dvorak H., Senger D. 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.[Medline]
  68. Sato K., Terada K., Sugiyama T., Takahashi S., Saito M., Moriyama M., Kakinuma H., Suzuki Y., Kato M., Kato T. Frequent overexpression of vascular endothelial growth factor gene in human renal cell carcinoma. Tohoku J. Exp. Med., 173: 355-360, 1994.[Medline]
  69. Golde D. W., Hocking W. G. Polycythemia: mechanisms and management. Ann. Intern. Med., 95: 71-87, 1981.
  70. Iliopoulos O., Jiang C., Levy A. P., Kaelin W.G., Goldberg M. A. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc. Natl. Acad. Sci. USA, 93: 10595-10599, 1996.[Abstract/Free Full Text]
  71. Gnarra J. R., Zhou S., Merrill M. J., Wagner J., Krumm A., Papavassiliou E., Oldfield E. H., Klausner R. D., Linehan W. M. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the VHL tumor suppressor gene product. Proc. Natl. Acad. Sci. USA, 93: 10589-10594, 1996.[Abstract/Free Full Text]
  72. Siemeister G., Weindel K., Mohrs K., Barleon B., Martiny-Baron G., Marme D. 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.[Abstract/Free Full Text]
  73. Maxwell P., Weisner M., Chang G-W., Clifford S., Vaux E., Pugh C., Maher E., Ratcliffe P. The von Hippel-Lindau gene product is necessary for oxygen-dependent proteolysis of hypoxia-inducible factor {alpha} subunits. Nature (Lond.), 399: 271-275, 1999.[Medline]
  74. Duan D. R., Pause A., Burgress W., Aso T., Chen D. Y. T., Garrett K. P., Conaway R. C., Conaway J. W., Linehan W. M., Klausner R. D. Inhibition of transcriptional elongation by the VHL tumor suppressor protein. Science (Wash. DC), 269: 1402-1406, 1995.[Abstract/Free Full Text]
  75. Pause A., Lee S., Worrell R. A., Chen D. Y. T., Burgess W. H., Linehan W. M., Klausner R. D. 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. USA, 94: 2156-2161, 1997.[Abstract/Free Full Text]
  76. Pause A., Peterson B., Schaffar G., Stearman R., Klausner R. Studying interactions of four proteins in the yeast two-hybrid system: structural resemblance of the pVHL/elongin BC/hCUL-2 complex with the ubiquitin ligase complex SKP1/cullin/F-box protein. Proc. Natl. Acad. Sci. USA, 96: 9533-9538, 1999.[Abstract/Free Full Text]
  77. Kibel A., Iliopoulos O., DeCaprio J. D., Kaelin W. G. Binding of the von Hippel-Lindau tumor suppressor protein to elongin B and C. Science (Wash. DC), 269: 1444-1446, 1995.[Abstract/Free Full Text]
  78. Lonergan K. M., Iliopoulos O., Ohh M., Kamura T., Conaway R. C., Conaway J. W., Kaelin W. G. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau protein requires binding to complexes containing elongins B/C and Cul2. Mol. Cell. Biol., 18: 732-741, 1998.[Abstract/Free Full Text]
  79. Kamura T., Koepp D. M., Conrad M. N., Skowyra D., Moreland R. J., Iliopoulos O., Lane W. S., Kaelin W. G. J., Elledge S. J., Conaway R. C., Harper J. W., Conaway J. W. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science (Wash. DC), 284: 657-661, 1999.[Abstract/Free Full Text]
  80. Kishida T., Stackhouse T. M., Chen F., Lerman M. I., Zbar B. 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.[Abstract/Free Full Text]
  81. Aso T., Lane W. S., Conaway J. W., Conaway R. C. Elongin (SIII). A multisubunit regulator of elongation by RNA polymerase II. Science (Wash. DC), 269: 1439-1443, 1995.[Abstract/Free Full Text]
  82. Kamura T., Sato S., Haque D., Liu L., Kaelin W. J., Conaway R., Conaway J. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev., 12: 3872-3881, 1998.[Abstract/Free Full Text]
  83. Bai C., Sen P., Hofmann K., Ma L., Goebl M., Harper J. W., Elledge S. J. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell, 86: 263-274, 1996.[Medline]
  84. Kipreos E. T., Lander L. E., Wing J. P., He W. W., Hedgecock E. M. cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family. Cell, 85: 829-839, 1996.[Medline]
  85. Mathias N., Johnson S., Winey M., Adams A., Goetsch L., Pringle J., Byers B., Goebl M. Cdc53p acts in concert with Cdc4p and Cdc34p to control the G1-to-S-phase transition and identifies a conserved family of proteins. Mol. Cell. Biol., 16: 6634-6643, 1996.[Abstract/Free Full Text]
  86. Willems A., Lanker S., Patton E., Craig K., Nason T., Mathias N., Kobayashi R., Wittenberg C., Tyers M. Cdc53 targets phosphorylated G1 cyclins for degradation by the ubiquitin proteolytic pathway. Cell, 86: 453-463, 1996.[Medline]
  87. Deshaies R. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu. Rev. Cell Dev. Biol., 15: 435-467, 1999.[Medline]
  88. Stebbins C. E., Kaelin W. G., Pavletich N. P. Structure of the VHL-elonginC-elonginB complex: implications for VHL tumor suppressor function. Science (Wash. DC), 284: 455-461, 1999.[Abstract/Free Full Text]
  89. Lisztwan J., Imbert G., Wirbelauer C., Gstaiger M., Krek W. The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev., 13: 1822-1833, 1999.[Abstract/Free Full Text]
  90. Iwai K., Yamanaka K., Kamura T., Minato N., Conaway R., Conaway J., Klausner R., Pause A. Identification of the von hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc. Natl. Acad. Sci. USA, 96: 12436-12441, 1999.[Abstract/Free Full Text]
  91. Semenza G. HIF-1 and human disease: one highly involved factor. Genes Dev., 14: 1983-1991, 2000.[Free Full Text]
  92. Semenza G. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu. Rev. Cell Dev. Biol., 15: 551-578, 1999.[Medline]
  93. Zhu H., Bunn F. Oxygen sensing and signaling: impact on the regulation of physiologically important genes. Respir. Physiol., 115: 239-247, 1999.[Medline]
  94. Ohh M., Park C. W., Ivan M., Hoffman M. A., Kim T-Y., Huang L. E., Chau V., Kaelin W. G. Ubiquitination of HIF requires direct binding to the von Hippel-Lindau protein ß domain. Nature Cell Biology, 2: 423-427, 2000.[Medline]
  95. Kamura T., Sato S., Iwain K., Czyzyk-Krzeska M., Conaway R. C., Conaway J. W. Activation of HIF1a ubiquitination by a reconstituted von Hippel-Lindau tumor suppressor complex. Proc. Natl. Acad. Sci. USA, 97: 10430-10435, 2000.[Abstract/Free Full Text]
  96. Cockman M., Masson N., Mole D., Jaakkola P., Chang G., Clifford S., Maher E., Pugh C., Ratcliffe P., Maxwell P. Hypoxia inducible factor-{alpha} binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J. Biol. Chem., 275: 25733-25741, 2000.[Abstract/Free Full Text]
  97. Tanimoto K., Makino Y., Pereira T., Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1{alpha} by the von Hippel-Lindau tumor suppressor protein. EMBO J., 19: 4298-4309, 2000.[Abstract]
  98. Ohh M., Takagi Y., Aso T., Stebbins C., Pavletich N., Zbar B., Conaway R., Conaway J., Kaelin W. J. Synthetic peptides define critical contacts between elongin C, elongin B, and the von hippel-lindau protein. J. Clin. Investig., 104: 1583-1591, 1999.[Medline]
  99. Clifford S., Cockman M., Smallwood A., Mole D., Woodward E., Maxwell P., Ratcliffe P., Maher E. Contrasting effects on HIF-1{alpha} regulation by disease-causing pVHL mutations correlate with patterns of tumorigenesis in von Hippel-Lindau disease. Hum. Mol. Genet., 10: 1029-1038, 2001.[Abstract/Free Full Text]
  100. Hoffman M., Ohh M., Yang H., Klco J., Ivan M., Kaelin W. J. von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum. Mol. Genet., 10: 1019-1027, 2001.[Abstract/Free Full Text]
  101. Ivan M., Kondo K., Yang H., Kim W., Valiando J., Ohh M., Salic A., Asara J., Lane W., Kaelin W. J. HIF{alpha} targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science (Wash. DC), 292: 464-468, 2001.[Abstract/Free Full Text]
  102. Jaakkola P., Mole D., Tian Y., Wilson M., Gielbert J., Gaskell S., Kriegsheim A., Hebestreit H., Mukherji M., Schofield C., Maxwell P., Pugh C., Ratcliffe P. Targeting of HIF-{alpha} to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science (Wash. DC), 292: 468-472, 2001.[Abstract/Free Full Text]
  103. Srinivas V., Zhang L., Zhu X., Caro J. Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor {alpha} (HIF-{alpha}) proteins. Biochem. Biophys. Res. Commun., 260: 557-561, 1999.[Medline]
  104. Kivirikko K. I., Myllyharju J. Prolyl 4-hydroxylases and their protein disulfide isomerase subunit. Matrix Biol., 16: 357-368, 1998.[Medline]
  105. Myllyharju J., Kivirikko K. Identification of a novel proline-rich peptide-binding domain in prolyl 4-hydroxylase. EMBO J., 18: 306-312, 1999.[Abstract]
  106. Ohh M., Yauch R. L., Lonergan K. M., Whaley J. M., Stemmer-Rachamimov A. O., Louis D. N., Gavin B. J., Kley N., Kaelin W. G., Iliopoulos O., Kaelin W. G. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol. Cell, 1: 959-968, 1998.[Medline]
  107. Koochekpour S., Jeffers M., Wang P., Gong C., Taylor G., Roessler L., Stearman R., Vasselli J., Stetler-Stevenson W., Kaelin W. J., Linehan W., Klausner R., Gnarra J., Vande Woude G. 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.[Abstract/Free Full Text]
  108. Pause A., Lee S., Lonergan K. M., Klausner R. D. The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc. Natl. Acad. Sci. USA, 95: 993-998, 1998.
  109. de Paulsen N., Brychzy A., Fournier M-C., Klausner R. D., Gnarra J. R., Pause A., Lee S. Role of transforming growth factor-{alpha} in VHL-/- clear cell renal carcinoma cell proliferation: a possible mechanism coupling von Hippel-Lindau tumor suppressor inactivation and tumorigenesis. Proc. Natl. Acad. Sci. USA, 13: 1387-1392, 2001.
  110. Knebelmann B., Ananth S., Cohen H., Sukhatme V. Transforming growth factor {alpha} is a target for the von Hippel-Lindau tumor suppressor. Cancer Res., 58: 226-231, 1998.[Abstract/Free Full Text]
  111. Reifenberger G., Reifenberger J., Bilzer T., Wechsler W., Collins V. 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.[Medline]
  112. Ramp U., Reinecke P., Gabbert H., Gerharz C. Differential response to transforming growth factor (TGF)-{alpha} and fibroblast growth factor (FGF) in human renal cell carcinomas of the clear cell and papillary types. Eur. J. Cancer, 36: 932-941, 2000.
  113. Chailler P., Briere N. Mitogenic effects of EGF/TGF alpha and immunolocalization of cognate receptors in human fetal kidneys. Biofactors, 7: 323-335, 1998.[Medline]
  114. Atlas I., Mendelsohn J., Baselga J., Fair W., Masui H., Kumar R. Growth regulation of human renal carcinoma cells: role of transforming growth factor {alpha}. Cancer Res., 52: 3335-3339, 1992.[Abstract/Free Full Text]
  115. Humes H., Beals T., Cieslinski D., Sanchez I., Page T. Effects of transforming growth factor-ß, transforming growth factor-{alpha}, and other growth factors on renal proximal tubule cells. Lab. Investig., 64: 538-545, 1991.[Medline]
  116. Petrides P., Bock S., Bovens J., Hofmann R., Jakse G. Modulation of pro-epidermal growth factor, pro-transforming growth factor {alpha} and epidermal growth factor receptor gene expression in human renal carcinomas. Cancer Res., 50: 3934-3939, 1990.[Abstract/Free Full Text]
  117. Adryan B., Decker H-J. H., Papas T. S., Hsu T. Tracheal development and the von Hippel-Lindau tumor suppressor homolog in Drosophila. Oncogene, 19: 2803-2811, 2000.[Medline]
  118. Aso T., Yamazaki K., Aigaki T., Kitajima S. Drosophila von hippel-lindau tumor suppressor complex possesses E3 ubiquitin ligase activity. Biochem. Biophys. Res. Commun., 276: 355-361, 2000.[Medline]
  119. Gao J., Naglich J. G., Laidlaw J., Whaley J. M., Seizinger B. R., Kley N. Cloning and characterization of a mouse gene with homology to the human von Hippel-Lindau disease tumor suppressor gene: implications for the potential organization of the human von Hippel-Lindau disease gene. Cancer Res., 55: 743-747, 1995.[Abstract/Free Full Text]
  120. Woodward E., Buchberger A., Clifford S., Hurst L., Affara N., Maher E. Comparative sequence analysis of the VHL tumor suppressor gene. Genomics, 65: 253-265, 2000.[Medline]
  121. Gnarra J., Ward J., Porter F., Wagne J., Devor D., Grinberg A., Emmert-Buck M., Westphal H., Klausner R., Linehan W. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc. Natl. Acad. Sci. USA, 94: 9102-9107, 1997.[Abstract/Free Full Text]
  122. Aplin J. Hypoxia and human placental development. J. Clin. Investig., 105: 559-560, 2000.[Medline]
  123. Rajakumar A., Conrad K. Expression, ontogeny, and regulation of hypoxia-inducible transcription factors in the human placenta. Biol. Reprod., 63: 559-569, 2000.[Abstract/Free Full Text]
  124. Adelman D., Gertsenstein M., Nagy A., Simon M., Maltepe E. Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev., 14: 3191-3203, 2000.[Abstract/Free Full Text]
  125. Genbacev O., Krtolica A., Kaelin W., Fisher S. Human cytotrophoblast expression of the von Hippel-Lindau protein is downregulated during uterine invasion in situ and upregulated by hypoxia in vitro. Dev. Biol., 233: 526-536, 2001.[Medline]
  126. Haase V., Glickman J., Socolovsky M., Jaenisch R. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc. Natl. Acad. Sci. USA, 98: 1583-1588, 2001.[Abstract/Free Full Text]
  127. Lee J-Y., Dong S-M., Park W-S., Yoo N-J., Kim C-S., Jang J-J., Chi J-G., Zbar B., Lubensky I., Linehan W., Vortmeyer A., Zhuang Z. Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res., 58: 504-508, 1998.[Abstract/Free Full Text]
  128. Krieg M., Marti H., Plate K. H. Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von hippel-lindau tumor suppressor gene loss of function. Blood, 92: 3388-3393, 1998.[Abstract/Free Full Text]
  129. Neumann H. P. H., Zbar B. Renal cysts, renal cancer and von Hippel-Lindau disease. Kidney Int., 51: 16-26, 1997.[Medline]
  130. Harris P., Ward C., Peral B., Hughes J. Autosomal dominant polycystic kidney disease: molecular analysis. Hum. Mol. Genet., 4: 1745-1749, 1995.[Abstract]
  131. Carone F., Bacallao R., Kanwar Y. Biology of disease: biology of Polycystic kidney disease. Lab. Investig., 70: 437-448, 1994.[Medline]
  132. Eng C., Crossey P., Mulligan L., Healey C., Houghton C., Prowse A., Chew S., Dahia P., O’Riordan J., Toledo S., Smith D., Maher E., Ponder B. Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumor suppressor gene in sporadic and syndromic phaeochromocytomas. J. Med. Genet., 32: 934-937, 1995.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
Proc. Natl. Acad. Sci. USAHome page
X. Lin, C. A. David, J. B. Donnelly, M. Michaelides, N. S. Chandel, X. Huang, U. Warrior, F. Weinberg, K. V. Tormos, S. W. Fesik, et al.
A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation
PNAS, January 8, 2008; 105(1): 174 - 179.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Renal Physiol.Home page
S. Turcotte, R. R. Desrosiers, and R. Beliveau
Hypoxia upregulates von Hippel-Lindau tumor-suppressor protein through RhoA-dependent activity in renal cell carcinoma
Am J Physiol Renal Physiol, February 1, 2004; 286(2): F338 - F348.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Renal Physiol.Home page
R. Debigare and S. R. Price
Proteolysis, the ubiquitin-proteasome system, and renal diseases
Am J Physiol Renal Physiol, July 1, 2003; 285(1): F1 - F8.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
A. V. Kuznetsova, J. Meller, P. O. Schnell, J. A. Nash, M. L. Ignacak, Y. Sanchez, J. W. Conaway, R. C. Conaway, and M. F. Czyzyk-Krzeska
von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination
PNAS, March 4, 2003; 100(5): 2706 - 2711.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
C. C. Hudson, M. Liu, G. G. Chiang, D. M. Otterness, D. C. Loomis, F. Kaper, A. J. Giaccia, and R. T. Abraham
Regulation of Hypoxia-Inducible Factor 1{alpha} Expression and Function by the Mammalian Target of Rapamycin
Mol. Cell. Biol., October 15, 2002; 22(20): 7004 - 7014.
[Abstract] [Full Text] [PDF]


Home page
Genes Dev.Home page
W. G. Kaelin Jr.
How oxygen makes its presence felt
Genes & Dev., June 15, 2002; 16(12): 1441 - 1445.
[Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
N. Sang, J. Fang, V. Srinivas, I. Leshchinsky, and J. Caro
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., May 1, 2002; 22(9): 2984 - 2992.
[Abstract] [Full Text] [PDF]


Home page
Cold Spring Harb Symp Quant BiolHome page
J.M. ARBEIT
Quiescent Hypervascularity Mediated by Gain of HIF-1{alpha} Function
Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 133 - 142.
[Abstract] [PDF]


This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, H.
Right arrow Articles by Kaelin, W. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, H.
Right arrow Articles by Kaelin, W. G., Jr.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation