scholarly journals Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

2016 ◽  
Vol 36 (12) ◽  
pp. 1803-1817 ◽  
Author(s):  
Fumihiko Okumura ◽  
Keiji Uematsu ◽  
Stuart D. Byrne ◽  
Mie Hirano ◽  
Akiko Joo-Okumura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Critical Role ◽  
Control Cell ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Protein Product ◽  
Von Hippel Lindau ◽  
Microarray Screening ◽  
Factor Α ◽  
Vhl Disease

pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxia-inducible factor α (HIF-α) for proteasomal degradation. Although HIF-α activation is necessary for VHL disease pathogenesis, constitutive activation of HIF-α alone did not induce renal clear cell carcinomas and pheochromocytomas in mice, suggesting the involvement of an HIF-α-independent pathway in VHL pathogenesis. Here, we show that the transcription factor B-Myb is a pVHL substrate that is degraded via the ubiquitin-proteasome pathway and that vascular endothelial growth factor (VEGF)- and/or platelet-derived growth factor (PDGF)-dependent tyrosine 15 phosphorylation of B-Myb prevents its degradation. Mice injected with B-Myb knockdown 786-O cells developed dramatically larger tumors than those bearing control cell tumors. Microarray screening of B-Myb-regulated genes showed that the expression of HIF-α-dependent genes was not affected by B-Myb knockdown, indicating that B-Myb prevents HIF-α-dependent tumorigenesis through an HIF-α-independent pathway. These data indicate that the regulation of B-Myb by pVHL plays a critical role in VHL disease.

scholarly journals Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice

2005 ◽  
Vol 25 (8) ◽  
pp. 3163-3172 ◽  
Author(s):  
Erinn B. Rankin ◽  
Debra F. Higgins ◽  
Jacqueline A. Walisser ◽  
Randall S. Johnson ◽  
Christopher A. Bradfield ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Line ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Vascular Tumors ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Arylhydrocarbon Receptor ◽  
Vhl Disease ◽  
Endothelial Growth Factor

ABSTRACT Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

scholarly journals VHL tumor suppressor regulates Cl−/HCO3− exchange and Na+/H+ exchange activities in renal carcinoma cells

2001 ◽  
Vol 5 (3) ◽  
pp. 119-128 ◽  
Author(s):  
S. ANANTH KARUMANCHI ◽  
LIANWEI JIANG ◽  
BERTRAND KNEBELMANN ◽  
ALAN K. STUART-TILLEY ◽  
SETH L. ALPER ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Mrna Level ◽  
Critical Role ◽  
Suppressor Gene ◽  
Mrna Levels ◽  
Differential Display Pcr ◽  
Von Hippel Lindau ◽  
Acid Load ◽  
Vhl Disease ◽  
Exchange Activity

Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are thought to play a critical role in the pathogenesis of both sporadic and VHL disease-associated clear-cell renal carcinomas (RCC). Differential display-PCR identified the AE2 anion exchanger as a candidate VHL target gene. AE2 mRNA and polypeptide levels were approximately threefold higher in 786-O VHL cells than in 786-O Neo cells. In contrast, Cl−/HCO3− exchange activity in 786-O VHL cells was 50% lower than in 786-O Neo cells. Since resting intracellular pH (pHi) values were indistinguishable, we postulated that Na+/H+ exchange activity (NHE) might be similarly reduced in 786-O VHL cells. NHE-mediated pHi recovery from acid load was less than 50% that in 786-O Neo cells, whereas hypertonicity-stimulated, amiloride-sensitive NHE was indistinguishable in the two cell lines. The NHE3 mRNA level was higher in 786-O VHL than 786-O Neo cells, but NHE1 mRNA levels did not differ. AE2 and NHE3 are the first transcripts reported to be upregulated by pVHL. Elucidation of mechanisms responsible for downregulation of both ion exchange activities will require further investigation.

Role of VHL Gene Mutation in Human Cancer

2004 ◽  
Vol 22 (24) ◽  
pp. 4991-5004 ◽  
Author(s):  
William Y. Kim ◽  
William G. Kaelin
Keyword(s):  
Tumor Suppressor ◽  
Target Genes ◽  
Human Cancer ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Tumor Formation ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome ◽  
Von Hippel Lindau

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.

scholarly journals pVHL Modification by NEDD8 Is Required for Fibronectin Matrix Assembly and Suppression of Tumor Development

2004 ◽  
Vol 24 (8) ◽  
pp. 3251-3261 ◽  
Author(s):  
Natalie H. Stickle ◽  
Jacky Chung ◽  
Jeffery M. Klco ◽  
Richard P. Hill ◽  
William G. Kaelin ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Three Dimensional ◽  
Suppressor Gene ◽  
Matrix Assembly ◽  
Von Hippel Lindau ◽  
Fibronectin Matrix ◽  
Matrix Expression ◽  
Vhl Disease ◽  
Hif Pathway

ABSTRACT Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the cause of the familial VHL disease and most sporadic renal clear-cell carcinomas (RCC). pVHL has been shown to play a role in the destruction of hypoxia-inducible factor α (HIF-α) subunits via ubiquitin-mediated proteolysis and in the regulation of fibronectin matrix assembly. Although most disease-causing pVHL mutations hinder the regulation of the HIF pathway, every disease-causing pVHL mutant tested to date has failed to promote the assembly of the fibronectin matrix, underscoring its potential importance in VHL disease. Here, we report that a ubiquitin-like molecule called NEDD8 covalently modifies pVHL. A nonneddylateable pVHL mutant, while retaining its ability to ubiquitylate HIF, failed to bind to and promote the assembly of the fibronectin matrix. Expression of the neddylation-defective pVHL in RCC cells, while restoring the regulation of HIF, failed to promote the differentiated morphology in a three-dimensional growth assay and was insufficient to suppress the formation of tumors in SCID mice. These results suggest that NEDD8 modification of pVHL plays an important role in fibronectin matrix assembly and that in the absence of such regulation, an intact HIF pathway is insufficient to prevent VHL-associated tumorigenesis.

scholarly journals The von Hippel-Lindau Protein pVHL Inhibits Ribosome Biogenesis and Protein Synthesis

2013 ◽  
Vol 288 (23) ◽  
pp. 16588-16597 ◽  
Author(s):  
Wen-Ting Zhao ◽  
Cheng-Fu Zhou ◽  
Xue-Bing Li ◽  
Yun-Fang Zhang ◽  
Li Fan ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Tumor Suppressor ◽  
Ribosome Biogenesis ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Nuclear Retention ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex ◽  
Ribosomal Protein S3 ◽  
Factor Α

pVHL, the product of von Hippel-Lindau (VHL) tumor suppressor gene, functions as the substrate recognition component of an E3-ubiquitin ligase complex that targets hypoxia inducible factor α (HIF-α) for ubiquitination and degradation. Besides HIF-α, pVHL also interacts with other proteins and has multiple functions. Here, we report that pVHL inhibits ribosome biogenesis and protein synthesis. We find that pVHL associates with the 40S ribosomal protein S3 (RPS3) but does not target it for destruction. Rather, the pVHL-RPS3 association interferes with the interaction between RPS3 and RPS2. Expression of pVHL also leads to nuclear retention of pre-40S ribosomal subunits, diminishing polysomes and 18S rRNA levels. We also demonstrate that pVHL suppresses both cap-dependent and cap-independent protein synthesis. Our findings unravel a novel function of pVHL and provide insight into the regulation of ribosome biogenesis by the tumor suppressor pVHL.

Molecular pathology of von Hippel–Lindau disease and the VHL tumour suppressor gene

2001 ◽  
Vol 3 (8) ◽  
pp. 1-27 ◽  
Author(s):  
Frances M. Richards
Keyword(s):  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Missense Mutations ◽  
Cancer Syndrome ◽  
Inherited Cancer ◽  
Von Hippel Lindau ◽  
Adrenal Chromaffin ◽  
Vhl Disease

von Hippel–Lindau (VHL) disease is a dominantly inherited cancer syndrome characterised by predisposition to multiple tumours of the eyes and central nervous system (haemangioblastomas), kidneys (renal cell carcinoma; RCC), adrenal chromaffin cells (phaeochromocytoma), and other organs. The VHL gene was isolated in 1993 and mutations or deletions in the VHL gene have been identified in the germline of nearly all tested individuals with VHL disease. Genotype–phenotype correlations have been observed: individuals with missense mutations are more likely to develop phaeochromocytoma than those with deletions or protein-truncating mutations are, and specific missense mutations at certain codons might not predispose to RCC. In accordance with its role as a tumour suppressor gene, the normal allele of the VHL gene is deleted, mutated or silenced by promoter methylation in the tumours from VHL patients, and in a large proportion of sporadic tumours of the same histological types as observed in VHL disease. Thus, the VHL gene is of major importance in the development of RCC in the general population. Recent advances in understanding the structure and function of the VHL protein (pVHL) have revealed insights into the different phenotypes, with indications that some retention of function might be required for predisposition to phaeochromocytoma. pVHL interacts with many cellular proteins, mainly via one of two protein-binding domains (α and β). The best-characterised interaction is that of pVHL with elongin C, which forms a complex with elongin B and Cullin 2 proteins. This complex has E3 ubiquitin ligase activity and promotes ubiquitin-mediated proteasomal degradation of the hypoxia-inducible factor 1α (HIF-1α) transcription factor under normal oxygen (normoxic) conditions. Loss of pVHL function leads to stabilisation of HIF-1 and expression under normoxic conditions of hypoxia-inducible genes including vascular endothelial growth factor (VEGF), which might explain the hypervascular phenotype of VHL tumours. Several other genes implicated in intra- and intercellular signalling and control of tumour growth are overexpressed in the absence of pVHL, but it is not yet clear which features of pVHL function are most significant for tumour suppression in different tissues. Further advances in understanding pVHL function might eventually enable development of specific therapies for prevention or treatment of VHL tumours and RCC.

Von Hippel–Lindau disease

2015 ◽  
Author(s):  
Thomas Connor ◽  
Patrick H. Maxwell
Keyword(s):  
Cellular Response ◽  
Familial Cancer ◽  
Critical Role ◽  
Clinical Manifestations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Von Hippel Lindau ◽  
Vhl Disease

Von Hippel–Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by germline mutations in the VHL tumour suppressor gene. The most frequent manifestations of VHL disease are retinal and central nervous system haemangioblastomas, clear cell renal cell carcinomas, and phaeochromocytomas. Genetic testing and active screening for clinical manifestations is now started in childhood and has greatly improved the prognosis for patients with VHL disease. The VHL protein plays a critical role in regulating the cellular response to changes in oxygen tension. Loss of VHL function results in constitutive activation of a range of angiogenic and metabolic pathways. New drug therapies have been developed that reverse some of the cellular consequences of VHL loss of function in kidney cancer.

Role of the VHL (von Hippel–Lindau) gene in renal cancer: a multifunctional tumour suppressor

2008 ◽  
Vol 36 (3) ◽  
pp. 472-478 ◽  
Author(s):  
Michelle J. Nyhan ◽  
Gerald C. O'Sullivan ◽  
Sharon L. McKenna
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Current Evidence ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex ◽  
Protein Functions ◽  
Factor Α

The VHL (von Hippel–Lindau) tumour-suppressor gene is inactivated in VHL disease and in sporadic cases of CCRCC [clear-cell RCC (renal cell carcinoma)]. pVHL (VHL protein) functions as part of an E3 ubiquitin ligase complex that targets proteins for proteasomal degradation. The best-characterized substrate is HIF-α (hypoxia-inducible factor-α). Loss of pVHL and subsequent up-regulation of HIF target genes has been attributed to the highly vascular nature of these neoplasms. However, pVHL does not just function as the executioner of HIF-α. Additional functions of pVHL that may be important in preventing CCRCC tumorigenesis have been identified, including primary cilium maintenance, assembly of the extracellular matrix and roles in the stabilization of p53 and Jade-1 (gene for apoptosis and differentiation in epithelia). Current evidence indicates that pVHL probably requires additional co-operating signalling pathways for CCRCC initiation and tumorigenesis.

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