The von Hippel-Lindau Tumor Suppressor Protein Is Required for Proper Assembly of an Extracellular Fibronectin Matrix

Ohh, Michael; Yauch, Robert L.; Lonergan, Kim M.; Whaley, Jean M.; Stemmer‐Rachamimov, Anat; Louis, David N.; Gavin, Brian J.; Kley, Nikolai; Kaelin, William G.; Iliopoulos, Othon

doi:10.1016/s1097-2765(00)80096-9

Cited by 433 publications

(407 citation statements)

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“…33 The present study reveals that VHL-mediated apoptosis of C6 glioma cells is accompanied by downregulation of Bcl-2. VHL is a multifunctional tumor suppressor protein exerting effects on hormone levels, 34 the extracellular matrix, [35][36][37] cell differentiation 38 and growth, 39 protease and protease inhibitor secretion, 40 the cytoskeleton and cell motility and invasiveness, mRNA stability, 41 the cell cycle, 42 and cell signaling, 43 all of which may play a role in the antitumour activity of VHL.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

et al. 2005

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The von Hippel-Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the a subunits of hypoxiainducible-factors responsible for stimulating tumor angiogenesis and glycolysis, and targeting them for ubiquitination and proteasomal destruction. Loss of pVHL leads to tumorigenesis and development of sporadic renal cell carcinomas and central nervous system hemangioblastomas. In the present study, we investigated whether engineered overexpression of pVHL in C6 glioma cells, which already express endogenous pVHL, would suppress the tumorigenicity of this particular tumor cell type. C6 cells overexpressing VHL displayed a reduced growth rate (70% inhibition) compared to the parental cell line when subcutaneously implanted in athymic (nu/nu) mice. Growth inhibition was associated with a 50% reduction in the number of tumor vessels and a 60% increase in tumor cell apoptosis, due in part to downregulation of HIF-1, VEGF, and the antiapoptotic factor Bcl-2, respectively. Gene transfer of VHL suppressed the growth of established C6 gliomas, and synergized with antisense HIF-1 to completely eradicate tumors. The data suggest that VHL gene therapy and/or agents that increase VHL expression could have utility in the treatment of gliomas, particularly when combined with agents that inhibit the expression or function of HIF-1.

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Section: Discussionmentioning

confidence: 99%

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

et al. 2005

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“…Aside from mediating HIF-a proteolysis, pVHL is involved in extracellular matrix (ECM) assembly matrix turnover, [42][43][44][45][46][47] the regulation of intracellular junctions, 48 NF-kB signaling, 49 the regulation of c-Met receptor responsiveness to hepatocyte growth factor (HGF) involving b-catenin 45,50 and the regulation of p53 transcriptional activity by suppressing Mdm2-mediated ubiquitination and nuclear export. 51 Furthermore, pVHL has been shown to regulate microtubule stability and cilia maintenance [52][53][54][55] and controls the activity of plant homeodomain protein Jade-1, 56,57 and atypical protein kinase C isoforms.…”

Section: Biological Functions Not Involving Hifmentioning

confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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“…pVHL30 has been shown previously to bind to at least four cellular proteins, elongin B, elongin C, Hs-CUL2, and ®bronectin (Duan et al, 1995a;Pause et al, 1997;Lonergan et al, 1998;Ohh et al, 1998). To test whether pVHL18 retains similar functions, 786-0 transgenic subclones transfected expressing pVHL25 or pVHL18 were metabolically labeled with 35 S-methionine, and lysates immunoprecipitated with IG32 monoclonal antibody.…”

Section: Resultsmentioning

confidence: 99%

“…Certain, but not all, tumor-derived mutants of pVHL are defective in binding to the B/C complex (Duan et al, 1995b;Kishida et al, 1995;Kibel et al, 1995). In addition, wild-type pVHL appears to interact with the human Hs-CUL2 protein (Pause et al, 1997;Lonergan et al, 1998), a member of a conserved gene family believed to play a role in ubiquitin-mediated protein degradation and growth control in lower eukaryotes. Binding of pVHL to HS-CUL2 appears to be dependent on binding of pVHL to elongin B/C , suggesting that the pVHL/B/C/Hs-CUL2 complex may a ect ubiquitination of target proteins regulating tumorigenic growth.…”

Section: Introductionmentioning

confidence: 99%

Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity

et al. 1999

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The VHL tumor suppressor gene has previously been reported to encode a protein of 213 amino acid residues. Here we report the identi®cation of a second major VHL gene product with an apparent molecular weight of 18 kD, pVHL18, which appears to arise from alternate translation initiation at a second AUG codon (codon 54) within the VHL open reading frame. In vitro and in vivo studies indicate that the internal codon in the VHL mRNA is necessary and su cient for production of pVHL18. pVHL18 can bind to elongin B, elongin C, and Hs-CUL2. When reintroduced into renal carcinoma cells that lack a wild-type VHL allele, pVHL18 suppresses basal levels of VEGF expression, restores hypoxiainducibility of VEGF expression, and inhibits tumor formation in nude mice. These data strongly support the existence of two distinct VHL gene products in VHL tumor suppression.

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The von Hippel-Lindau Tumor Suppressor Protein Is Required for Proper Assembly of an Extracellular Fibronectin Matrix

Cited by 433 publications

References 44 publications

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

The VHL tumor suppressor and HIF: insights from genetic studies in mice

Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity

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