The von Hippel–Lindau tumor suppressor gene product represses oncogenic β-catenin signaling in renal carcinoma cells

Peruzzi, Benedetta; Athauda, Gagani; Bottaro, Donald P.

doi:10.1073/pnas.0606850103

Cited by 94 publications

(79 citation statements)

References 58 publications

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“…It nonetheless is intriguing that MET, CDK6, and MAP2K1 have been linked previously to kidney cancer biology. Germline MET mutations cause papillary renal carcinoma, and there is recent evidence that VHL loss, which is linked tightly to clear cell histology, also leads to c-MET activation (13)(14)(15)(16). VHL loss in renal epithelial cells, but not in other cell types tested, leads to up-regulation of Cyclin D1 (17,18), which is a partner protein for Cdk6 and Cdk4.…”

Section: Discussionmentioning

confidence: 99%

“…VHL loss leads, indirectly, to activation of kinases that are important for renal carcinoma tumorigenesis (reviewed in ref. 7), including kinases present within the tumor cells themselves, such as EGFR (11,12), c-Met (13)(14)(15)(16), and cyclin D1-associated kinases (17,18), and those associated with blood vessels, such as kinase insert domain receptor and platelet-derived growth factor receptor. Kidney cancer is refractory to most conventional chemotherapeutics and radiotherapy but often responds, at least temporarily, to drugs that inhibit kinase insert domain receptor.…”

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confidence: 99%

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Kinase requirements in human cells: III. Altered kinase requirements inVHL−/− cancer cells detected in a pilot synthetic lethal screen

Bommi-Reddy

Almeciga

Sawyer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

137

117

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Clear cell renal carcinomas are the most common form of kidney cancer and frequently are linked to biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. The VHL gene product, pVHL, has multiple functions including directing the polyubiquitylation of the HIF transcription factor. We screened 100 shRNA vectors, directed against 88 kinases, for their ability to inhibit the viability of VHL؊/؊ renal carcinoma cells preferentially compared with isogenic cells in which pVHL function was restored. shRNAs for ''hits'' identified in the primary screen were interrogated in secondary screens that included shRNA titration studies. Multiple shRNAs against CDK6, MET, and MAP2K1 (also known as MEK1) preferentially inhibited the viability of 786-O and RCC4 VHL؊/؊ cells compared with their wild-type pVHL-reconstituted counterparts. The sensitivity of pVHL-proficient cells to these shRNAs was not restored upon HIF activation, suggesting that loss of an hypoxia-inducible factor (HIF)-independent pVHL function formed the basis for selectivity. A small-molecule Cdk4/6 inhibitor displayed enhanced activity against VHL؊/؊ renal carcinoma cells, suggesting that in some cases hits from shRNA screens such as described here might translate into therapeutic targets.essential kinases ͉ shRNA screens ͉ VHL ͉ kidney cancer ͉ therapeutics

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Kinase requirements in human cells: III. Altered kinase requirements inVHL−/− cancer cells detected in a pilot synthetic lethal screen

Bommi-Reddy

Almeciga

Sawyer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

137

117

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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%

“…Similarly, Evans et al 107 demonstrated that knockdown of pVHL resulted in E-cadherin suppression via HIF-dependent induction of E2 box-dependent transcriptional repressors Snail and SIP1, and Krishnamachary et al 108 reported that HIF-1 activation in VHL-deficient cells downregulated Ecadherin, led to the loss of cell-cell adhesion and promoted epithelial to mesenchymal transition through the induction of transcriptional repressors TCF3, ZFHX1A and ZFHX1B/SIP1. Therefore, cellular changes, such as loss of intercellular junctions and epithelial de-differentiation involving HIFdependent as well as HIF-independent molecular pathways 48,[106][107][108] in addition to HIF-dependent and -independent alterations in p53 or NF-kB activity, 34,35,49,51 HGF signaling, 45,50,109 and modifications in ECM turnover and re-modeling [42][43][44][45][46][47] create the molecular environment for the development CC-RCC, which most likely requires additional genetic events. The importance of HIF activation in CC-RCC pathogenesis and growth is furthermore underscored by experimental and clinical studies, which demonstrated that inhibition of HIF-a translation by pharmacological targeting of mTOR correlated with reduced tumor growth, 110 and that increased expression of certain HIF target genes, such as CXCR4, as well as E-cadherin suppression was associated with disease progression.…”

Section: Pvhl and Renal Cell Cancermentioning

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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“…34 However, in contrast to adult sporadic clear cell renal cell carcinoma with a high percentage of VHL gene mutations and loss of heterozygosity of the VHL gene region, in renal cell carcinoma in young patients, VHL gene mutations are absent. 8 In this regard, the lack of b-catenin accumulation especially in the clear cell renal cell carcinomas in our current study is in accordance with our previous demonstration of the absence of VHL mutations and rarity of VHL alterations in renal cell carcinomas in young patients.…”

Section: Discussionmentioning

confidence: 97%

Wnt signaling pathway analysis in renal cell carcinoma in young patients

et al. 2007

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Renal cell carcinomas in young patients constitute a morphologically and genetically heterogeneous group. Twenty percent belong to the newly recognized Xp11.2 translocation-associated family and rare tumors arise from nephroblastoma. Aberrant Wnt signaling through b-catenin mutation has been implicated in nephroblastoma pathogenesis and has been found to synergize with WT1 mutations. To characterize Wnt signaling activity in renal cell carcinomas in young patients, we gathered 34 tumors (three clear cell, ten Xp11.2 translocation associated, five papillary, two chromophobe, two collecting duct, one neuroblastoma associated, eight unclassified renal cell carcinomas, and three carcinomas combined with nephroblastoma) from patients less than 22 years. Expression of b-catenin, its homologue c-catenin, and of WT1 was assessed by immunohistochemistry in 30 tumors, and sequence analysis of CTNNB1, CTNNG1, and WT1 genes was performed in 25 tumors. Cytoplasmic b-catenin accumulation was demonstrated in two papillary carcinomas, one neuroblastoma-associated carcinoma, and two carcinomas arising from nephroblastoma. The pattern of c-catenin expression paralleled that of b-catenin but its signal intensity was lower in 22, equal in 7, and stronger only in 1 tumor, respectively. Four tumors showed nuclear WT1 expression. One Xp11.2 translocationassociated carcinoma presented a rare intronic CTNNB1 single nucleotide polymorphism and cytoplasmic b-catenin accumulation. There were no further CTNNB1 or CTNNG1 sequence alterations. A WT1 mutation was found in the nephroblastoma component of a carcinoma arising from nephroblastoma. These findings suggest Wnt signaling pathway activation only in a minority of renal cell carcinomas in young patients. CTNNB1 mutations are rare events. Cytoplasmic b-catenin accumulation in an Xp11.2-associated carcinoma suggests potential interaction of Wnt signaling components with microphthalmia transcription factor family also in Xp11.2 translocation carcinomas. WT1 mutation in the nephroblastoma component of a mixed-type renal cell carcinoma provides direct evidence for clonal independence of nephroblastoma and carcinoma components in this exceptional tumor.

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The von Hippel–Lindau tumor suppressor gene product represses oncogenic β-catenin signaling in renal carcinoma cells

Abstract: Loss of vonc-Met ͉ hepatocyte growth factor ͉ renal cell carcinoma

Cited by 94 publications

References 58 publications

Kinase requirements in human cells: III. Altered kinase requirements inVHL−/− cancer cells detected in a pilot synthetic lethal screen

Kinase requirements in human cells: III. Altered kinase requirements inVHL−/− cancer cells detected in a pilot synthetic lethal screen

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

Wnt signaling pathway analysis in renal cell carcinoma in young patients

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