Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter

Zatyka, Malgorzata

doi:10.1136/jmg.39.7.463

Cited by 35 publications

(27 citation statements)

References 49 publications

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“…Nevertheless, the 11 bp duplication is located within the promoter region of the VHL gene, in the vicinity of the main transcription initiation site (Kuzmin et al 1995), and within the putative binding site of several transcription factors (Zatyka et al 2002). We therefore investigated the possibility that the variant could alter transcription of the gene from the affected allele.…”

Section: Resultsmentioning

confidence: 99%

Molecular analysis of two uncharacterized sequence variants of the VHL gene

et al. 2006

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Mutations in the VHL gene cause von Hippel-Lindau disease, a cancer predisposing syndrome characterized by a variety of benign and malignant neoplasms. We report the molecular characterization of two sequence variants of the VHL gene: a synonymous substitution c.462 A>C in exon 2 and a duplication of 11 bp in the promoter region (c.-65_ -55dup11). The first variant is a pathogenic mutation because, although it does not change the sense of the affected codon, it causes skipping of exon 2 in the affected allele by altering the splicing consensus site at the 3¢ end of exon 2. The 11 bp duplication represents a nonpathogenic variant. In fact, although it affects a critical region of the VHL promoter, it was found in healthy controls, and we show that carrier individuals express both VHL alleles at equimolar levels. Our data underline the importance of careful evaluation of the potential pathogenicity of sequence variants that may not belong to the obvious disease-causing mutation categories, or that affect relevant regulatory regions. mRNA analysis will be required to ultimately resolve this issue.

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Section: Resultsmentioning

confidence: 99%

Molecular analysis of two uncharacterized sequence variants of the VHL gene

et al. 2006

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“…This genetic insight linked several lines of evidence that indicated that the HIF-a was subjected to PHD-mediated hydroxylation under normoxic conditions, requiring the presence of iron, 2-oxoglutarate, PHDs, and oxygen. Once modified by the-OH group, HIF-a can be captured by pVHL, which then delivers HIF-a to an E3-ubiquitin ligase complex through binding of Elongins B and C, and subsequent proteasomal degradation [Hon et al, 2002;Ivan et al, 2001;Jaakkola et al, 2001;Jiang et al, 2003;Maxwell et al, 1999;Min et al, 2002;Vengellur et al, 2003;Wykoff et al, 2000;Yu et al, 2001;Zatyka et al, 2002;Zhu and Bunn, 2001]. The interplay of these proteins, centered on the presence of an-OH group, results in a direct molecular oxygen sensor.…”

Section: The Vhl Gene and Functionmentioning

confidence: 99%

“…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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“…Evenmore, Sp1 expression is temporally and spatially regulated during nephrogenesis. Interestingly, Sp1 was reported as a regulator of the Wilms' tumor (WT1) and Von Hippel -Lindau (VHL) tumor suppressor genes 44,45 that are involved in renal cancers.…”

Section: Human Gtctcactcttgttgcccaggctggagtgccat---------------------mentioning

confidence: 99%

Common regulatory elements in the polycystic kidney disease 1 and 2 promoter regions

et al. 2005

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The PKD1 and PKD2 genes are mutated in patients with autosomal dominant polycystic kidney disease (ADPKD), a systemic disease, with the formation of renal cysts as main clinical feature. The genes are developmentally regulated and aberrant expression of PKD1 or PKD2 leads to cystogenesis. To date, however, the transcription factors regulating expression of these genes have hardly been studied. To identify conserved putative transcription factor-binding sites, we cloned and characterized the 5 0 -flanking regions of the murine and canine Pkd1 genes and performed a multispecies comparison by including sequences from the human and Fugu rubripes orthologues as well as the Pkd2 promoters from mouse and human. Sequence analysis revealed a variety of conserved putative binding sites for transcription factors and no TATA-box element. Nine elements were conserved in the mammalian Pkd1 promoters: AP2, E2F, EBox, EGRF, ETS, MINI, MZF1, SP1, and ZBP-89. Interestingly, six of these elements were also found in the mammalian Pkd2 promoters. Deletion studies with the mouse Pkd1 promoter showed that a B280 bp fragment is capable of driving luciferase reporter gene expression, whereas reporter constructs containing larger fragments of the Pkd1 promoter showed a lower activity. Furthermore, mutating a potential E2F-binding site within this 280 bp fragment diminished the reporter construct activity, suggesting a role for E2F in regulating cell cycle-dependent expression of the Pkd1 gene. Our data define a functional promoter region for Pkd1 and imply that E2F, EGRF, Ets, MZF1, Sp1, and ZBP-89 are potential key regulators of PKD1 and PKD2 in mammals.

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Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter

Cited by 35 publications

References 49 publications

Molecular analysis of two uncharacterized sequence variants of the VHL gene

Molecular analysis of two uncharacterized sequence variants of the VHL gene

Genetic analysis of von Hippel-Lindau disease

Common regulatory elements in the polycystic kidney disease 1 and 2 promoter regions

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