scholarly journals Bilateral Pheochromocytomas in a Patient with Y175C Von Hippel-Lindau Mutation

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Olga Astapova ◽  
Anindita Biswas ◽  
Alessandra DiMauro ◽  
Jacob Moalem ◽  
Stephen R. Hammes
Keyword(s):  
Tumor Development ◽  
Screening Guidelines ◽  
Von Hippel Lindau ◽  
Hypoxic Conditions ◽  
Oxygen Conditions ◽  
Vhl Protein ◽  
Function Relationship ◽  
Vhl Disease ◽  
Relationship Of ◽  
Dependent Mechanism

Von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is characterized by metachronously occurring tumors including pheochromocytoma, renal cell carcinoma (RCC), and hemangioblastoma. Although VHL disease leads to reduced life expectancy, its diagnosis is often missed and tumor screening guidelines are sparse. VHL protein acts as a tumor suppressor by targeting hypoxia-inducible factors (HIFs) for degradation through an oxygen-dependent mechanism. VHL mutants with more severely reduced HIF degrading function carry a high risk of RCC, while mutants with preserved HIF degrading capacity do not cause RCC but still lead to other tumors. VHL disease is classified into clinical types (1 and 2A-2C) based on this genotype-phenotype relationship. We report a case of bilateral pheochromocytomas and no other VHL-related tumors in a patient with Y175C VHL and show that this mutant preserves the ability to degrade HIF in normal oxygen conditions but, similar to the wild-type VHL protein, loses its ability to degrade HIF under hypoxic conditions. This study adds to the current understanding of the structure-function relationship of VHL mutations, which is important for risk stratification of future tumor development in the patients.

scholarly journals von Hippel-Lindau Disease: an Update

2019 ◽  
Vol 7 (4) ◽  
pp. 227-235 ◽  
Author(s):  
Eamonn R Maher ◽  
Richard N Sandford
Keyword(s):  
Natural History ◽  
Patient Outcomes ◽  
Molecular Characterisation ◽  
Von Hippel Lindau ◽  
Functional Characterisation ◽  
History Of ◽  
Vhl Protein ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Improve Patient

Abstract Purpose of Review In this review, we discuss the key molecular and clinical developments in VHL disease that have the potential to impact on the natural history of the disease and improve patient outcomes. Recent Findings Identifiable mutations in VHL underlie most cases of VHL and define clear genotype-phenotype correlations. Detailed clinical and molecular characterisation has allowed the implementation of lifelong screening programmes that have improved clinical outcomes. Functional characterisation of the VHL protein complex has revealed its role in oxygen sensing and the mechanisms of tumourigenesis that are now being exploited to develop novel therapies for VHL and renal cancer. Summary The molecular and cellular landscape of VHL-associated tumours is revealing new opportunities to modify the natural history of the disease and develop therapies. Drugs are now entering clinical trials and combined with improved clinical and molecular diagnosis, and lifelong surveillance programmes, further progress towards reducing the morbidity and mortality associated with VHL disease is anticipated.

scholarly journals The Endothelial Landscape and Its Role in Von Hippel–Lindau Disease

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2313
Author(s):  
Isabel de Rojas-P ◽  
Virginia Albiñana ◽  
Lyudmyla Taranets ◽  
Lucía Recio-Poveda ◽  
Angel M. Cuesta ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Vascular Diseases ◽  
Hereditary Disease ◽  
In Vitro Assays ◽  
Second Hit ◽  
Von Hippel Lindau ◽  
Vhl Protein ◽  
Von Hippel Lindau Disease

Von Hippel–Lindau disease (VHL) is a rare hereditary disease characterized by the predisposal to develop different types of highly vascularized tumors. VHL patients carry a VHL mutation that causes partial lack of functional VHL protein (pVHL) in all cells, and a total lack thereof in cells harboring a second hit mutation. Absence of pVHL generates a prolonged state of pseudo-hypoxia in the cell due to accumulation of hypoxia inducible factor, an important transcription factor regulating pro-tumorigenic genes. The work here presented focuses on characterizing the endothelium of VHL patients, by means of blood outgrowth endothelial cells (BOECs). Transcriptome analysis of VHL-derived BOECs, further supported by in vitro assays, shows that these cells are at a disadvantage, as evidenced by loss of cell adhesion capacity, angiogenesis defects, and immune response and oxidative metabolic gene downregulation, which induce oxidative stress. These results suggest that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development. These findings contribute to shedding light on the vascular landscape of VHL patients preceding the second hit mutation in the VHL gene. This knowledge could be useful in searching for new therapies for these patients and other vascular diseases.

Results of a high-throughput screen to identify compounds that modulate VHL proteostasis.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 369-369
Author(s):  
Zhiyong Ding ◽  
Peter German ◽  
Shanshan Bai ◽  
Meng Gao ◽  
Mary M. Sobieski ◽  
...  
Keyword(s):  
Clinical Effect ◽  
Fluorescent Protein ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Full Length ◽  
Inhibitory Effects ◽  
Von Hippel Lindau ◽  
Vhl Protein ◽  
A Cell ◽  
Vhl Disease

369 Background: Mutated von Hippel Lindau (VHL) protein causes disease in sporadic renal cell carcinoma (RCC), and in the eponymous hereditary VHL disease. We developed and tested a cell-based screening tool to identify compounds that stabilize or upregulate full-length, point mutated VHL, and potentially reverse the disease phenotype. Methods: The 786-0 cell line was infected with full-length W117A mutated VHL linked to a C-terminal Venus fluorescent protein. This VHL-W117A-Venus line was used to screen the Prestwick drug library and was tested against the known proteasome inhibitors MG132 and bortezomib. Western blot validation and evaluation of downstream functional readouts, including HIF and GLUT1 levels, were performed. Results: The proteasome inhibitors bortezomib and MG132, and the Prestwick compounds 8-azaguanine, thiostrepton and thioguanosine were found to reliably upregulate VHL-W117A-Venus in 786-0 cells. Thiostrepton has also been recognized as having proteasome inhibitory effects. 8-azaguanine was found to downregulate HIF2α levels, and was augmented by the presence of VHL W117A. VHL p30 band intensities varied as a function of compound used, suggesting alternate post-translational processing. In addition, nuclear-cytoplasmic localization of pVHL varied amongst the different compounds, additionally suggesting unique effects of each of the agents on VHL homeostasis. Conclusions: We have successfully identified compounds that stabilize mutated VHL, including several proteasome inhibitors. It is possible that proteasome inhibition will have a specific clinical effect on patients with point-mutated pVHL. Further work is currently underway to further test this hypothesis in animal xenograft studies using cell lines containing various mutated VHL isoforms, and clinical trials using next-generation proteasome inhibitors are being explored.

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 Cerebellar hemangioblastomas: A study of the immunoprofile of neoplastic stromal component

2004 ◽  
Vol 61 (3) ◽  
pp. 273-282
Author(s):  
Desanka Tasic ◽  
Dragan Dimov ◽  
Milos Kostov ◽  
Srbislav Ilic ◽  
Dojcin Dojcinov ◽  
...  
Keyword(s):  
Mast Cells ◽  
Stromal Cells ◽  
Protein Function ◽  
Neuron Specific Enolase ◽  
Factor Xiiia ◽  
Von Hippel Lindau ◽  
Stromal Component ◽  
S 100 ◽  
Vhl Protein ◽  
Vhl Disease

Background. Central nervous system hemangioblastomas (HBs) are uncommon highly vascularized tumors that are predominantly found in the cerebellum. They occur sporadically or in association with von Hippel-Lindau (VHL) disease. HBs are of unknown histogenesis, and the origin of stromal cells is still a subject of debate. The aim of this study was to investigate the immunoprofile of neoplastic stromal component, and to determine whether the profile of the expression of immunomarkers used can contribute to the elucidation of the histogenesis of HBs. Methods. A series of eight cerebellar HBs were histochemically examined for the detection of mast cells and immunohistochemically for the expression of factor VIII-related antigen (FVIII-RAg), CD34, vimentin, factor XIIIa (FXIIIa), S-100 protein, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) neurofilaments (NF), synaptophysin, chromogranin, and somatostatin. Results. Mast cells were present in all hemangioblastomas, and were particularly abundant in one tumor. Immunohistochemically, intense reactivity for vimentin and NSE in the stromal cells was constantly seen. Immunoreactivity with S-100 protein and FXIIIa was variable, but generally many HBs stromal cells were negative for these markers. However, stromal cells were uniformly negative for FVIII-RAg in all HBs investigated. They were negative for CD34 GFAP, NF, synaptophysin, chromogranin, as well as somatostatin. GFAP-positivity of the occasional stromal type cells, located only peripherally, was interpreted as "pseudopositivity". Conclusion. The immunoprofile of neoplastic stromal component in this study suggested a possible origin from undifferentiated multipotential mesenchymal cells. High expression of NSE (glycolytic and hypoxia-inducible enzyme) in the HBs stromal cells might be related to the loss of the VHL protein function.

Familial tumour syndromes: von Hippel–Lindau disease

2017 ◽  
Author(s):  
Hiroshi Kanno ◽  
Joachim P. Steinbach
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Laboratory Data ◽  
Von Hippel Lindau ◽  
Vhl Protein ◽  
Von Hippel Lindau Disease ◽  
The Central Nervous System ◽  
Microsurgical Techniques ◽  
Vhl Disease ◽  
Hif Pathway

Von Hippel–Lindau (VHL) disease, an autosomal dominant familial tumour syndrome, is often associated with haemangioblastoma of the central nervous system. In the presence of oxygen, VHL protein serves to prevent the accumulation of hypoxia-inducible factor (HIF) protein by targeting it to the proteasomal pathway, while biallelic inactivation of the VHL gene blocks degradation of HIF and leads to constitutive activation of the HIF pathway although oxygen is present. HIF-target genes are involved in angiogenesis, proliferation, and metabolism enabling tumour growth. Haemangioblastoma is a highly vascularized, begin tumour commonly associated with a cyst, but it is linked with neurological morbidity and mortality based on its location and multiplicity. Haemangioblastoma in VHL is diagnosed according to symptoms and signs, past and family histories, laboratory data, neuroradiological findings, pathological findings, and genetic testing. Surgical treatment is usually the most recommended therapy for haemangioblastomas, and using well-defined microsurgical techniques, the majority can be resected safely.

scholarly journals EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance

2019 ◽  
Vol 116 (34) ◽  
pp. 16997-17006 ◽  
Author(s):  
Shuijie Li ◽  
Javier Rodriguez ◽  
Wenyu Li ◽  
Petra Bullova ◽  
Stuart M. Fell ◽  
...  
Keyword(s):  
Chemotherapy Resistance ◽  
Von Hippel Lindau ◽  
Extracellular Signal ◽  
Familial Pheochromocytoma ◽  
Oxygen Sensitive ◽  
Vhl Protein ◽  
Sensitive Function ◽  
Induced Apoptosis ◽  
Vhl Disease

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel–Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we identified an oxygen-sensitive function of VHL that is abolished by VHL type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFα or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant.

Structure–property–function relationship of fluorescent conjugated microporous polymers

2021 ◽  
Author(s):  
M. G. Monika Bai ◽  
H. Vignesh Babu ◽  
V. Lakshmi ◽  
M. Rajeswara Rao
Keyword(s):  
Long Range ◽  
Structure Property ◽  
Porous Organic Polymers ◽  
Aggregation Induced Emission ◽  
Microporous Polymers ◽  
Exciton Migration ◽  
Wide Range ◽  
Function Relationship ◽  
Relationship Of ◽  
Conjugated Microporous Polymers

Fluorescent porous organic polymers are a unique class of materials owing to their strong aggregation induced emission, long range exciton migration and permanent porosity, thus envisioned to possess a wide range of applications (sensing, OLEDs).

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