Gene array of VHL mutation and hypoxia shows novel hypoxia-induced genes and that cyclin D1 is a VHL target gene

Wykoff, Charles C.; Sotiriou, Christos; Cockman, Matthew E.; Ratcliffe, Peter J.; Maxwell, Patrick H.; Liu, E; Harris, Adrian L.

doi:10.1038/sj.bjc.6601657

Cited by 90 publications

(90 citation statements)

References 24 publications

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“…Using a significance threshold of two fold differential expression, we identified 30 genes that were differentially regulated. Although other groups have used similar strategies to identify pVHL targets (Wykoff et al, 2000(Wykoff et al, , 2004Zatyka et al, 2002;Jiang et al, 2003;Staller et al, 2003) only four (VEGF, CCND1, transgelin and DEC1) of the 30 genes had been previously identified as a pVHL target. We selected 11 of the 26 novel target genes for further analysis and verified the microarray expression results by real-time quantitative RT-PCR or Western analysis in all cases.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of global mRNA expression patterns by oligonucleotide microarray technology or SAGE analyses has provided an unbiased approach to identifying pVHL target genes (Wykoff et al, 2000;Zatyka et al, 2002;Jiang et al, 2003;Wykoff et al, 2004). As the identification of novel pVHL targets might provide further insights into mechanisms of pVHL tumour suppressor activity, we used high-density oligonucleotide arrays to identify differentially expressed genes in pVHL wild-type and null RCC cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Identification of novel VHL target genes and relationship to hypoxic response pathways

et al. 2005

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Upregulation of hypoxia-inducible factors HIF-1 and HIF-2 is frequent in human cancers and may result from tissue hypoxia or genetic mechanisms, in particular the inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene (TSG). Tumours with VHL inactivation are highly vascular, but it is unclear to what extent HIFdependent and HIF-independent mechanisms account for pVHL tumour suppressor activity. As the identification of novel pVHL targets might provide insights into pVHL tumour suppressor activity, we performed gene expression microarray analysis in VHL-wild-type and VHL-null renal cell carcinoma (RCC) cell lines. We identified 30 differentially regulated pVHL targets (26 of which were 'novel') and the results of microarray analysis were confirmed in all 11 novel targets further analysed by real-time RT-PCR or Western blotting. Furthermore, nine of 11 targets were dysregulated in the majority of a series of primary clear cell RCC with VHL inactivation. Three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. The significance for pVHL function of two further genes upregulated by wild-type pVHL was initially unclear, but re-expression of GNG4 (G protein gamma-4 subunit/ guanine nucleotide-binding protein-4) and MLC2 (myosin light chain) in a RCC cell line suppressed tumour cell growth. pVHL regulation of CDKN1C, SPARC and GNG4 was not mimicked by hypoxia, whereas for six of 11 novel targets analysed (including DOC-2/DAB2 and MLC2) the effects of pVHL inactivation and hypoxia were similar. For GPR56 there was evidence of a tissuespecific hypoxia response. Such a phenomenon might, in part, explain organ-specific tumorigenesis in VHL disease. These provide insights into mechanisms of pVHL tumour suppressor function and identify novel hypoxiaresponsive targets that might be implicated in tumorigenesis in both VHL disease and in other cancers with HIF upregulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of novel VHL target genes and relationship to hypoxic response pathways

et al. 2005

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“…[115][116][117][118] HIF-2 has been proposed to preferentially regulate molecular pathways critical for renal cell growth, such as signaling through the TGF-a/epidermal growth factor receptor pathway, cyclin D1 and the c-Myc proto-oncogene. [119][120][121][122][123][124] Taken together, there is substantial evidence that HIF-1 and HIF-2 have diverse functions with regard to VHL renal tumorigenesis, which could be exploited therapeutically, and may be strongly context dependent. 125 Not much is known about the role of HIF-3a in VHL-associated tumorigenesis.…”

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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“…VHL analysis in C. elegans has produced strong evidence that a group of genes is regulated by pVHL in a manner independent of oxygen levels [Bishop et al, 2004]. Furthermore, multiple groups have reported microarray analyses in mammalian cell lines that indicate a role for pVHL independent of its interaction with HIF [Bluyssen et al, 2004;Bommi-Reddy et al, 2008;Jiang et al, 2003;Wykoff 2000Wykoff , 2004Zatyka et al, 2002]. Other roles of pVHL include microtubule stability [Hergovich et al, 2003], microtubule orientation [Schermer et al, 2006], cilia formation [Esteban et al, 2006;Lolkema et al, 2008;Lutz and Burk, 2006;Schermer 2006;Thoma et al, 2007], regulation of senescence [Young et al, 2008], cytokine signalling [Wu et al, 2007], collagen IV regulation [Grosfeld et al, 2007;Kurban et al, 2008], and assembly of a normal extracellular fibronectin matrix [Ohh et al, 1998].…”

Section: The Vhl Gene and Functionmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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Gene array of VHL mutation and hypoxia shows novel hypoxia-induced genes and that cyclin D1 is a VHL target gene

Cited by 90 publications

References 24 publications

Identification of novel VHL target genes and relationship to hypoxic response pathways

Identification of novel VHL target genes and relationship to hypoxic response pathways

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

Genetic analysis of von Hippel-Lindau disease

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