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.

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 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 von Hippel-Lindau Tumor Suppressor Protein Regulates the Assembly of Intercellular Junctions in Renal Cancer Cells through Hypoxia-Inducible Factor–Independent Mechanisms

2006 ◽  
Vol 66 (3) ◽  
pp. 1553-1560 ◽  
Author(s):  
Maria J. Calzada ◽  
Miguel A. Esteban ◽  
Monica Feijoo-Cuaresma ◽  
Maria C. Castellanos ◽  
Salvador Naranjo-Suárez ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Renal Cancer ◽  
Hypoxia Inducible Factor ◽  
Intercellular Junctions ◽  
Tumor Suppressor Protein ◽  
Von Hippel Lindau

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.

From oxygen sensing to angiogenesis: Targeting the hypoxia signaling pathway in metastatic kidney cancer

2020 ◽  
Vol 77 (24) ◽  
pp. 2064-2073
Author(s):  
Clement Chung
Keyword(s):  
Tumor Suppressor ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Clear Cell ◽  
Cell Cancer ◽  
Hypoxia Inducible Factor ◽  
Von Hippel Lindau ◽  
Hypoxia Signaling

Abstract Purpose This article summarizes examples of current and emerging therapies that target the hypoxia and angiogenesis signaling pathways in the clear cell type of renal cell cancer (RCC), with an emphasis on the hypoxia signaling pathway. Summary Mammalian cells transduce signals of decreased oxygen to hypoxia inducible factor (HIF), an intracellular heterodimer that mediates the adaptation of normal and tumor cells to oxygen deprivation. HIF is frequently overexpressed in cancer cells and is involved in the transcriptional activation of many genes essential for cell invasion, migration, survival, and angiogenesis (including vascular endothelial growth factor [VEGF]). Moreover, HIF confers resistance to cytotoxic chemotherapy and radiation therapy and is associated with poor prognosis in patients with cancer. Blocking the activity of HIF inhibits the expression of VEGF and oncogenic pathways, resulting in the inhibition of tumor growth. Interestingly, activation of oncogenes and/or inactivation of tumor suppressor genes (eg, the gene encoding von Hippel-Lindau [VHL] tumor suppressor protein) can activate tumorigenesis even with normal levels of oxygen, providing support for the notion that the HIF-VHL-VEGF axis is amenable to targeted therapies for the treatment of RCC. This article highlights the current understanding of the hypoxia signaling pathway and its relevance to RCC development. Pharmacologic agents targeting the hypoxia and angiogenesis signaling pathways are discussed. Conclusion Development of novel therapeutic agents that target the hypoxia and angiogenesis signaling pathways holds promise in the management of metastatic clear cell RCC.

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.

Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia

Blood ◽  
2009 ◽  
Vol 113 (25) ◽  
pp. 6449-6460 ◽  
Author(s):  
Ellen van Rooijen ◽  
Emile E. Voest ◽  
Ive Logister ◽  
Jeroen Korving ◽  
Thorsten Schwerte ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Chemical Activation ◽  
Amino Acid Level ◽  
Hypoxia Inducible Factor ◽  
Erythroid Differentiation ◽  
Suppressor Gene ◽  
Mrna Levels ◽  
Hypoxic Response ◽  
Hematopoietic Stem ◽  
Von Hippel Lindau

Abstract We have generated 2 zebrafish lines carrying inactivating germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene ortholog vhl. Mutant embryos display a general systemic hypoxic response, including the up-regulation of hypoxia-induced genes by 1 day after fertilization and a severe hyperventilation and cardiophysiologic response. The vhl mutants develop polycythemia with concomitantly increased epo/epor mRNA levels and erythropoietin signaling. In situ hybridizations reveal global up-regulation of both red and white hematopoietic lineages. Hematopoietic tissues are highly proliferative, with enlarged populations of c-myb+ hematopoietic stem cells and circulating erythroid precursors. Chemical activation of hypoxia-inducible factor signaling recapitulated aspects of the vhl−/− phenotype. Furthermore, microarray expression analysis confirms the hypoxic response and hematopoietic phenotype observed in vhl−/− embryos. We conclude that VHL participates in regulating hematopoiesis and erythroid differentiation. Injections with human VHLp30 and R200W mutant mRNA demonstrate functional conservation of VHL between mammals and zebrafish at the amino acid level, indicating that vhl mutants are a powerful new tool to study genotype-phenotype correlations in human disease. Zebrafish vhl mutants are the first congenital embryonic viable systemic vertebrate animal model for VHL, representing the most accurate model for VHL-associated polycythemia to date. They will contribute to our understanding of hypoxic signaling, hematopoiesis, and VHL-associated disease progression.

scholarly journals Loss of Von Hippel–Lindau (VHL) Tumor Suppressor Gene Function: VHL–HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC)

2021 ◽  
Vol 22 (18) ◽  
pp. 9795
Author(s):  
Hyunho Kim ◽  
Byoung Yong Shim ◽  
Seung-Ju Lee ◽  
Ji Youl Lee ◽  
Hyo-Jin Lee ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Suppressor ◽  
Cell Carcinoma ◽  
Tumor Suppressor Gene ◽  
Renal Cell ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Von Hippel Lindau ◽  
Combination Strategies ◽  
Hif Pathway

Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel–Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL–HIF–VEGF/VEGFR pathway, which involves the von Hippel–Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL–HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL–HIF pathway.

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