The multifaceted von Hippel–Lindau tumour suppressor protein

Robinson, Claire M.; Ohh, Michael

doi:10.1016/j.febslet.2014.02.026

Cited by 89 publications

(65 citation statements)

References 84 publications

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“…Loss-of-functional VHL (and therefore stabilization of HIF1a) predisposes to various malignancies (44) and overexpression/overactivation of HIF1a is correlated with poor prognosis in a number of cancers (45). In zebrafish, we observed this deregulation to be accompanied by MTH1 upregulation, indicating an important function for this nononcogenic addition enzyme in this context.…”

Section: Discussionmentioning

confidence: 67%

Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition

et al. 2016

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Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity.Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1a response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. Cancer Res; 76(8); 2366-75. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 67%

Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition

et al. 2016

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“…Besides, a number of sporadic cancers, including ccRCC, are strongly associated with VHL reduced expression and/or loss-of-function mutations (Gnarra et al 1994;Cassol and Mete, 2015). The best characterized pVHL function is ubiquitination followed by proteasome degradation of target proteins (Robinson and Ohh, 2014). In particular, the pVHL forms a multiprotein complex with elongins B and C, cullin 2 and Rbx-1, which functions as a ubiquitinligating enzyme (E3 ligase).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, the pVHL forms a multiprotein complex with elongins B and C, cullin 2 and Rbx-1, which functions as a ubiquitinligating enzyme (E3 ligase). Within the complex pVHL is responsible for recognition of substrates, among which the members of the hypoxia-inducible factor α (HIFα) family (Robinson and Ohh, 2014). In complex with HIFβ, HIFα act as transcription factors enhancing the expression of a variety of genes involved in the adaptive response to hypoxic condition and tumor progression as well, such as genes that promote neoangiogenesis (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…transforming growth factor-α, TGF-α) (Robinson and Ohh, 2014;Balamurugan, 2016). In addition, VHL has been shown to affect several hypoxia-independent cellular functions, including extracellular matrix formation, spindle microtubule stability, cilia formation, epithelial-to-mesenchymal (EMT) transition, cell proliferation, apoptosis and DNA damage response (Robinson and Ohh, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Deregulated expression of VHL mRNA variants in papillary thyroid cancer

Baldini

Tuccilli

Arlot‐Bonnemains

et al. 2017

Molecular and Cellular Endocrinology

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Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI).The analysis of VHL mRNA in tumor tissues, compared to normal matched tissues, revealed that its expression was either up-or down-regulated in the majority of PTC. In particular, V1 and V2 mRNA levels were altered, respectively, in 78 (81.3%) and 65 (67.7%) out of the 96 PTCs analyzed. A significant positive correlation between the two mRNA variants was observed (p<0.001). Univariate analysis documented the lack of association between each variant and clinicopathological parameters such as age, tumor size, histology, TNM stage, lymph node metastases, and BRAF mutational status. However, a strong correlation was found between altered V1 or V2 mRNA levels and DFI. Multivariate regression analysis indicated higher V1 mRNA values, along with lymph node metastases at diagnosis, as independent prognostic factors predicting DFI. In conclusion, the data reported demonstrate that VHL gene expression is deregulated in the majority of PTC tissues. Of particular interest is the apparent protective role exerted by VHL transcripts against PTC recurrences.

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“…VHL diseases are associated with various tumor types, including clear cell renal cell carcinomas, CNS and retinal hemangioblastomas, pheochromocytomas, and pancreatic neuroendocrine tumors, in addition to pancreatic and renal cysts (2,3). The VHL tumor suppressor protein (pVHL) forms a ternary complex with elongin C and elongin B termed VHL-elongin B/C (VCB) complex, which resembles the yeast Skp1-Cullen-1/Cdc53-F-box protein complex (4). The VCB complex and the similar Skp1-Cullen-1/ Cdc53-F-box protein complex both possess ubiquitin ligase activities and are capable of targeting proteins for proteasomal degradation.…”

mentioning

confidence: 99%

pVHL Negatively Regulates Antiviral Signaling by Targeting MAVS for Proteasomal Degradation

Zhang

et al. 2015

The Journal of Immunology

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The von Hippel–Lindau (VHL) gene is a well-defined tumor suppressor linked to human heredity cancer syndromes. As a component of the VHL-elongin B/C E3 ligase complex, pVHL performs its tumor function by targeting proteins for proteasomal degradation. It is largely unknown whether pVHL functions in antiviral immunity. In this article, we identify that pVHL negatively regulates innate antiviral immunity, which acts mainly by inducing degradation of mitochondrial antiviral-signaling protein (MAVS, also known as Cardif, IPS-1, or VISA). Overexpression of pVHL abrogated the cellular response to viral infection, whereas knockdown of pVHL exerted the opposite effect. pVHL targeted the K420 residue of MAVS to catalyze the formation of K48-linked polyubiquitin chains, leading to proteasomal degradation of MAVS. After viral infection, Mavs levels remained low in wild type zebrafish embryos but became much higher in vhl-deficient (vhl−/−) zebrafish embryos. Higher MAVS levels correlated with a greatly exaggerated antiviral response. In this work, we demonstrate that pVHL exhibits a previously unknown role in innate antiviral immunity.

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The multifaceted von Hippel–Lindau tumour suppressor protein

Cited by 89 publications

References 84 publications

Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition

Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition

Deregulated expression of VHL mRNA variants in papillary thyroid cancer

pVHL Negatively Regulates Antiviral Signaling by Targeting MAVS for Proteasomal Degradation

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