Primary Cilium Formation Requires von Hippel-Lindau Gene Function in Renal-Derived Cells

Lutz, Mallory S.; Burk, Robert D.

doi:10.1158/0008-5472.can-06-0501

Cited by 128 publications

(90 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 The Burk and Benzing labs do not observe this connection in their cell systems. 7,9 In different cells, Lutz et al 7 report cilia regulation by the murine-short isoform of VHL, Vhlh-p18; however, we observe no human VHL-p19 localization in the cilium, and significantly reduced functioning of this organelle in our calcium-flow experiments. Thus, our data suggest that cilia function in renal carcinoma cells is dependent on two domains in VHL, residues 1-53, known as the acidic domain, and residues 95-123, previously implicated in microtubule binding and tumor suppression.…”

Section: Discussioncontrasting

confidence: 60%

Allele-specific regulation of primary cilia function by the von Hippel–Lindau tumor suppressor

et al. 2007

View full text Add to dashboard Cite

Patients with von Hippel -Lindau (VHL) disease often develop VHLÀ/À kidney cysts, which possibly progress into clear-cell renal carcinomas (ccRCCs). Recent data link the VHL gene product to formation of the primary cilium, an organelle that extends apically into the renal lumen. Exactly how VHL induces ciliogenesis or function is unknown. Here, we demonstrate that ciliary assembly and mechanotransduction is rapidly restored in VHLÀ/À ccRCC cells upon ectopic reconstitution of wild-type -but not variant alleles of -VHL. These data support and expand recent studies implicating a role for VHL in the initiation of ciliogenesis. Furthermore, reduction of cellular levels of VHL in this cell system was associated with fewer ciliated cells, suggesting a role for VHL in ciliary maintenance.

show abstract

Section: Discussioncontrasting

confidence: 60%

Allele-specific regulation of primary cilia function by the von Hippel–Lindau tumor suppressor

et al. 2007

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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,

show abstract

“…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. [58][59][60][61][62] Other pVHL targets include a KRAB-A domain protein, VHLak, repressing HIF transcriptional activity, 63 de-ubiquitinating enzymes, 64 the large subunit of RNA polymerase II 65 and the RNA-binding protein hnRNP A2.…”

Section: Biological Functions Not Involving Hifmentioning

confidence: 99%

“…102 More recent studies have proposed that pVHL is essential for cilium maintenance. [52][53][54][55]103 pVHL was reported to cooperate with GSK3b in an interlinked signaling pathway that maintains the primary cilium. 53 Schermer et al 54 demonstrated that pVHL localizes to the monocilia of kidney cells, interacts with Par3-Par6-aPKC and controls ciliogenesis via coordinated extension of microtubules toward the cell periphery and Esteban et al 103 proposed a role for HIF in cilium maintenance.…”

Section: Pvhl and Renal Cell Cancermentioning

confidence: 99%

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

2008

View full text Add to dashboard Cite

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 ...

show abstract

Primary Cilium Formation Requires von Hippel-Lindau Gene Function in Renal-Derived Cells

Cited by 128 publications

References 19 publications

Allele-specific regulation of primary cilia function by the von Hippel–Lindau tumor suppressor

Allele-specific regulation of primary cilia function by the von Hippel–Lindau tumor suppressor

Genetic analysis of von Hippel-Lindau disease

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

Contact Info

Product

Resources

About