The role of von Hippel-Lindau tumor suppressor protein and hypoxia in renal clear cell carcinoma

2004 ◽  
Vol 287 (1) ◽  
pp. F1-F6 ◽  
Author(s):  
Roxana I. Sufan ◽  
Michael A. S. Jewett ◽  
Michael Ohh
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Renal Clear Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex ◽  
Vhl Protein

The majority of kidney cancers are caused by the mutation of the von Hippel-Lindau ( VHL) tumor suppressor gene. VHL protein (pVHL) is part of an E3 ubiquitin ligase complex called VEC that is composed of elongin B, elongin C, cullin 2, NEDD8, and Rbx1. VEC targets a hypoxia-inducible factor (HIF) transcription factor for ubiquitin-mediated destruction selectively in the presence of oxygen. In the absence of wild-type pVHL, as in VHL patients or in the majority of sporadic clear cell renal cell carcinomas, HIF-responsive genes are inappropriately activated even under normoxia. Recent insights into the molecular mechanisms regulating the function of pVHL, and thereby HIF, in the context of kidney cancer are the focus of this review.

scholarly journals Downregulation of integrins by von Hippel-Lindau (VHL) tumor suppressor protein is independent of VHL-directed hypoxia-inducible factor alpha degradation

2008 ◽  
Vol 86 (3) ◽  
pp. 227-234 ◽  
Author(s):  
Qingzhou Ji ◽  
Robert D. Burk
Keyword(s):  
Tumor Suppressor ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Intercellular Junctions ◽  
Suppressor Gene ◽  
Wild Type ◽  
Von Hippel Lindau ◽  
Degradation Activity ◽  
Factor Alpha ◽  
Vhl Tumor Suppressor Protein

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in the majority of clear-cell renal cell carcinomas (RCCs). It was previously shown that VHL decreased the abundance of integrins α2, α5, and β1, which is consistent with VHL-associated changes in cell–cell and cell – extracellular matrix adhesions. We investigated the mechanism by which VHL downregulates integrins. Although VHL can target hypoxia-inducible factor alpha (HIFα) subunits for degradation, VHL-dependent reduction of integrins was independent of O2 concentration and HIFα levels. VHL reduced the half-lives of integrins, and this activity was blocked by proteasomal inhibition. Although ectopically expressed FLAG-VHL retained HIFα degradation activity, it neither downregulated integrins nor promoted adherens and tight intercellular junctions, in contrast to expressed wild-type VHL. Moreover, integrins co-immunoprecipitated with wild-type VHL, but not FLAG-VHL. These data indicate that the downregulation of integrins by VHL is distinct from the regulation of HIFα subunits by VHL, and suggests that the loss of this activity contributes to VHL-associated RCC development through disruption of adherens and tight junctions.

scholarly journals Playing Tag with HIF: The VHL Story

2002 ◽  
Vol 2 (3) ◽  
pp. 131-135 ◽  
Author(s):  
Sherri K. Leung ◽  
Michael Ohh
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
E3 Ubiquitin Ligase ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Matrix Assembly ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex

Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL is the cause of inherited VHL disease and is associated with sporadic kidney cancer. pVHL is found in a multiprotein complex with elongins B/C, Cul2, and Rbx1 forming an E3 ubiquitin ligase complex called VEC. This modular enzyme targets theαsubunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated destruction. Consequently, tumour cells lacking functional pVHL overproduce the products of HIF-target genes such as vascular endothelial growth factor (VEGF), which promotes angiogenesis. This likely accounts for the hypervascular nature of VHL-associated neoplasms. Although pVHL has been linked to the cell-cycle, differentiation, and the regulation of extracellular matrix assembly, microenvironment pH, and tissue invasiveness, this review will focus on the recent insights into the molecular mechanisms governing the E3 ubiquitin ligase function of VEC.

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.

scholarly journals Key Role for Activin B in Cellular Transformation after Loss of the von Hippel-Lindau Tumor Suppressor

2009 ◽  
Vol 29 (7) ◽  
pp. 1707-1718 ◽  
Author(s):  
Ingrid Wacker ◽  
Martin Sachs ◽  
Karl Knaup ◽  
Michael Wiesener ◽  
Jörg Weiske ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Transforming Growth Factor ◽  
Clear Cell ◽  
Cell Transformation ◽  
Hypoxia Inducible Factor ◽  
Cellular Transformation ◽  
Transforming Growth Factor Β ◽  
Suppressor Gene ◽  
Normal Kidney ◽  
Von Hippel Lindau

ABSTRACT The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in clear cell renal cell carcinomas (RCC), leading to the activation of hypoxia-inducible factor (HIF)-mediated gene transcription. Several VHL/HIF targets, such as glycolysis, angiogenesis, cell growth, and chemotaxis of tumor cells, have been implicated in the transformed phenotype of RCC-regulating properties. Here, we show that VHL suppresses key features of cell transformation through downregulation of the HIF-dependent expression of activin B, a member of the transforming growth factor β superfamily. Activin B expression is repressed by restoration of VHL in VHL-deficient RCC cells and upregulated by hypoxia. RCC tumor samples show increased expression of activin B compared to that in the normal kidney. VHL increases cell adhesion to the extracellular matrix, promotes cell flattening, and reduces invasiveness. These effects are completely phenocopied by RNA interference-mediated knockdown of activin B and reverted by treatment with recombinant activin B. Finally, knockdown of activin B reduces tumor growth of RCC cells in nude mice. Our data indicate that activin B is a key mediator of VHL/HIF-induced transformation in RCC.

scholarly journals Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer

2020 ◽  
Vol 6 (3) ◽  
pp. 27 ◽  
Author(s):  
Dominik A. Barth ◽  
Felix Prinz ◽  
Julia Teppan ◽  
Katharina Jonas ◽  
Christiane Klec ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Protein Coding ◽  
Rna Molecules ◽  
Von Hippel Lindau ◽  
Hypoxic Conditions ◽  
Main Regulator ◽  
Upstream Regulators

Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.

Phosphatidylinositol 3′-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1α and vascular endothelial growth factor expression

2011 ◽  
Vol 300 (6) ◽  
pp. H2169-H2176 ◽  
Author(s):  
Yan Xue ◽  
Nan-Lin Li ◽  
Jing-Yue Yang ◽  
Yan Chen ◽  
Lu-Lu Yang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tumor Suppressor ◽  
Active Form ◽  
Hypoxia Inducible Factor ◽  
Pi3k Pathway ◽  
Rho Proteins ◽  
Phosphatidylinositol 3 Kinase ◽  
Von Hippel Lindau ◽  
Phosphatidylinositol 3

We have previously demonstrated the roles of RhoA, Rac1, and Cdc42 in hypoxia-driven angiogenesis. However, the role of oncogenes in hypoxia signaling is poorly understood. Given the importance of Rho proteins in the hypoxic response, we hypothesized that Rho family members could act as mediators of hypoxic signal transduction. We investigated the cross-talk between hypoxia and oncogene-driven signal transduction pathways and explored the role of Rac1 on hypoxia-induced hypoxia-inducible factor (HIF)-1α and VEGF expression. Since the phosphatidylinositol 3′-kinase (PI3K) pathway is involved in signal transduction of many oncogenes, we explored the role of PI3K on Rac1-mediated expression of HIF-1α and VEGF in hypoxia. We showed that LY-294002, a PI3K inhibitor, suppressed HIF-1α and VEGF induction under hypoxic conditions by up to 50%. Activation of Rac1 resulted in an upregulation of hypoxia-induced HIF-1α expression, which was blocked by LY-294002. These data suggested that Rac1 is an intermediate in the PI3K-mediated induction of HIF-1α. Interestingly, there was a significant downregulation of the tumor suppressor genes p53 and von Hippel-Lindau tumor suppressor (VHL) in cells expressing a constitutively active form of Rac1. Rac1-mediated inhibition of p53 and VHL could therefore be implicated in the upregulation of HIF-1α expression.

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 Clear cell chondrosarcoma in Von Hippel-Lindau disease

2019 ◽  
Vol 19 (1) ◽  
pp. 41-45 ◽  
Author(s):  
Koen M. A. Dreijerink ◽  
Rachel S. van Leeuwaarde ◽  
Wenzel M. Hackeng ◽  
Rachel H. Giles ◽  
Wendy W. J. de Leng ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Clear Cell ◽  
Immunohistochemical Analysis ◽  
Tumor Grade ◽  
Suppressor Gene ◽  
Clear Cell Chondrosarcoma ◽  
Von Hippel Lindau ◽  
Vhl Protein ◽  
Von Hippel Lindau Disease ◽  
A Cell

Abstract A diagnosis of clear cell chondrosarcoma of the ulna was made in a patient with Von Hippel-Lindau disease (VHL). After surgery, genetic analysis of the tumor tissue showed loss of heterozygosity at the VHL gene locus. Immunohistochemical analysis confirmed loss of expression of the VHL protein in the tumor cells. In addition, abundant Cyclin D1 expression in the tumor was observed. Chondrosarcoma has been described before in a VHL patient and VHL protein expression has been correlated to tumor grade in a series of sporadic chondrosarcomas. In this report, we show that clear cell chondrosarcoma may be a rare but canonical VHL manifestation through a cell-autonomous mechanism involving somatic loss-of-heterozygosity of the VHL tumor suppressor gene. We discuss the relevance of this observation with regard to the pathogenesis of clear cell chondrosarcoma in the context of VHL.

The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 α (HIF-1α) activity: involvement in myeloma-induced angiogenesis

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4464-4475 ◽  
Author(s):  
Simona Colla ◽  
Sara Tagliaferri ◽  
Francesca Morandi ◽  
Paolo Lunghi ◽  
Gaetano Donofrio ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Family Member ◽  
Tumor Suppressor Gene ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Direct Interaction ◽  
Suppressor Gene

Angiogenesis has a critical role in the pathophysiology of multiple myeloma (MM); however, the molecular mechanisms underlying this process are not completely elucidated. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) has been recently implicated in solid tumors as a repressor of angiogenesis. In this study, we found that ING4 expression in MM cells was correlated with the expression of the proangiogenic molecules interleukin-8 (IL-8) and osteopontin (OPN). Moreover, we demonstrate that ING4 suppression in MM cells up-regulated IL-8 and OPN, increasing the hypoxia inducible factor-1α (HIF-1α) activity and its target gene NIP-3 expression in hypoxic condition. In turn, we show that the inhibition of HIF-1α by siRNA suppressed IL-8 and OPN production by MM cells under hypoxia. A direct interaction between ING4 and the HIF prolyl hydroxylase 2 (HPH-2) was also demonstrated. Finally, we show that ING4 suppression in MM cells significantly increased vessel formation in vitro, blunted by blocking IL-8 or OPN. These in vitro observations were confirmed in vivo by finding that MM patients with high IL-8 production and microvascular density (MVD) have significantly lower ING4 levels compared with those with low IL-8 and MVD. Our data indicate that ING4 exerts an inhibitory effect on the production of proangiogenic molecules and consequently on MM-induced angiogenesis.

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