The von Hippel–Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery

Lolkema, Martijn P.; Mehra, Niven; Jorna, Anita S.; Beest, Moniek van; Giles, Rachel; Voest, Emile E.

doi:10.1016/j.yexcr.2004.07.016

Cited by 53 publications

(44 citation statements)

References 18 publications

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“…For example, Esteban et al 6 claim HIF responsible for the development of cilia, whereas we and others fail to find this connection. 7 -9 The KC12 cells we use here are devoid of HIF1/2a 10 and subsequently do not show upregulated mRNA levels of HIF targets VEGF and GLUT1 in RT-PCR experiments (unpublished data), arguing that cilia regulation is indeed a HIF-independent function of VHL. Furthermore, our data support the notion put forward by the Krek group 8 that regulating primary cilia requires residues 95-123, previously implicated in microtubule stability.…”

Section: Discussionmentioning

confidence: 83%

“…KC12TR and KC12TR/VHL-TO cell lines were generated and induced with 1 mg/ml doxycycline (Sigma-Aldrich, St Louis, MO, USA) as previously described. 10 Transfections were performed using Fugene-6 (Boehringer Mannheim, Ingelheim, Germany) (HEK293T) or by electroporation (KC12 cells: 270 V, 1.0 mF).…”

Section: Cell Culturementioning

confidence: 99%

“…In addition to diffuse cytoplasmic staining, VHL clearly localized to cilia extending form basal bodies stained with g-tubulin ( Figure 1a). To confirm the effect of VHL on ciliogenesis in our preferred cell system, we used a stable cell line derived from a VHL patient engineered to re-express empty vector (KC12TR) or VHL (KC12TR/VHL-TO) upon induction by doxycycline 10 and observed rapid assembly of cilia (Figures 1b -c). Because the kinetics of VHL-dependent cilia growth is unknown, ciliary assembly/ extension in induced KC12TR/VHL-TO cells was measured over time.…”

Section: Vhl-mediated Cilia Functionmentioning

confidence: 99%

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

et al. 2007

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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.

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Section: Discussionmentioning

confidence: 83%

Section: Cell Culturementioning

confidence: 99%

Section: Vhl-mediated Cilia Functionmentioning

confidence: 99%

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

et al. 2007

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“…This network could disturb local hemodynamics, facilitating the production of cyst fluid, and the increased local concentration of growth factors could stimulate epithelial cell proliferation (21). A second possibility involves the stabilization of microtubules, which is a well-documented but less extensively studied function of the VHL protein (64,65). In the absence of VHL, primary cilia are absent or defective (66).…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways

Jiao

Molin³

et al. 2011

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

591

552

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More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 ± 4.6, 27 ± 12, 16 ± 7.6, and 2.9 ± 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel-Lindau gene (VHL), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (β-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.

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“…The phosphorylation of pVHL affects the half-life of the protein, increases its stability and enhances the activity of p53 (a protein interactor with the pVHL). The interaction between pVHL and p53 protein involves the residues from 155 to 213 of pVHL including the β domain of this protein, which exists in the pVHL isoforms 2 (Lolkema et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Aurora A kinase interacts with and phosphorylates VHL protein

Ferchichi¹,

Arlot²,

Cremet³

et al. 2012

Biologia

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Abstract:The serine/threonin kinase Aurora A is an oncoprotein, whereas von Hippel-Lindau protein (pVHL) is a tumor suppressor protein. Both proteins have the same localization during mitosis: in the mitotic spindle and the centrosome. These two proteins also have common functions, such as the regulation of the cell cycle, the stability of the mitotic spindle and both intervene in the functioning of centrosomes. In this study we have analyzed the interaction between Aurora A and pVHL with immunoprecipitation and in vitro phosphorylation experiments. We have confirmed that the immunoprecipitation of pVHL from Hek 293 cell extracts were coupled with Aurora A. In addition, the interaction between the two proteins has been tested by analyzing the phosphorylation of pVHL in vitro by Aurora A. The results revealed that pVHL was phosphorylated by Aurora A. In conclusion, the study demonstrated that Aurora A interacts with and phosphorylates pVHL. Given the role of these two proteins in cell division as well as their status in cancer, this interaction requires further investigation.

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The von Hippel–Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery

Cited by 53 publications

References 18 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

Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways

Aurora A kinase interacts with and phosphorylates VHL protein

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