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.

A Case of Type 1 von Hippel-Lindau (VHL) Disease associated with VHL Germline Mutation

2006 ◽  
Vol 21 (3) ◽  
pp. 239 ◽  
Author(s):  
Jeong Hoon Seo ◽  
Jae Hong Yang ◽  
Pyoung Lak Choi ◽  
Yu Lee Kim ◽  
Young Sik Choi ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Von Hippel Lindau ◽  
Vhl Disease

scholarly journals Novel genotype–phenotype correlations in five Chinese families with Von Hippel–Lindau disease

2018 ◽  
Vol 7 (7) ◽  
pp. 870-878 ◽  
Author(s):  
Qiuli Liu ◽  
Gang Yuan ◽  
Dali Tong ◽  
Gaolei Liu ◽  
Yuting Yi ◽  
...  
Keyword(s):  
Malignant Neoplasms ◽  
Missense Mutations ◽  
Chinese Families ◽  
Von Hippel Lindau ◽  
Disease Phenotypes ◽  
Mri Scans ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease

Context Von Hippel–Lindau (VHL) disease manifests as a variety of benign and malignant neoplasms. Previous studies of VHL disease have documented several genotype–phenotype correlations; however, many such correlations are still unknown. Increased identification of new mutations and patients with previously described mutations will allow us to better understand how VHL mutations influence disease phenotypes. Patients and design A total of 45 individuals from five unrelated families were evaluated, of which 21 patients were either diagnosed with VHL disease or showed strong evidence related to this disease. We compared the patients’ gene sequencing results with their medical records including CT or MRI scans, eye examinations and laboratory/pathological examinations. Patients were also interviewed to obtain information regarding their family history. Results We identified four missense mutations: c.239G>T (p.Ser80Ile), linked with VHL Type 2B, was associated with renal cell carcinoma, pheochromocytoma and hemangioma in the cerebellum; c.232A>T (p.Asn78Tyr) manifested as RCC alone and likely caused VHL Type 1; c.500G>A (p.Arg167Gln) mutation was more likely to cause VHL Type 2 than Type 1 as it preferentially induced Pheo and HB in the retina, cerebellum and spinal cord; c.293A>G (p.Try98Cys) was associated with Pheo and thus likely induced VHL Type 2. Conclusions Characterizing VHL disease genotype–phenotype correlations can enhance the ability to predict the risk of individual patients developing different VHL-related phenotypes. Ultimately, such insight will improve the diagnostics, surveillance and treatment of VHL patients. Precis Four missense mutations in VHL have been identified in 21 individuals when five unrelated Chinese families with VHL disease were analyzed; VHL mutations are highly associated with unique disease phenotypes.

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.

Familial tumour syndromes

2010 ◽  
pp. 482-493
Author(s):  
George Samandouras
Keyword(s):  
Tuberous Sclerosis ◽  
Giant Cell ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Subependymal Giant Cell Astrocytoma ◽  
Von Hippel Lindau ◽  
Vhl Disease ◽  
Giant Cell Astrocytoma

Chapter 8.18 covers familial tumour syndromes, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), von Hippel-Lindau (VHL) disease and capillary haemangioblastoma, tuberous sclerosis and subependymal giant cell astrocytoma (SEGA), and Lhermitte-Duclos disease.

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 Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease

2019 ◽  
Vol 104 (9) ◽  
pp. 3826-3834 ◽  
Author(s):  
Shahida K Flores ◽  
Ziming Cheng ◽  
Angela M Jasper ◽  
Keiko Natori ◽  
Takahiro Okamoto ◽  
...  
Keyword(s):  
Suppressor Gene ◽  
The Cancer Genome Atlas ◽  
Exon 2 ◽  
Von Hippel Lindau ◽  
Familial Pheochromocytoma ◽  
Cancer Genome Atlas ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Spliced Variant

Abstract Context von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. Objective We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. Design We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases. Results We identified a synonymous VHL variant (c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. Conclusion A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.

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 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.

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