The von Hippel–Lindau Tumor Suppressor Gene

Kondo, Keiichi; Kaelin, William G.

doi:10.1006/excr.2000.5139

Cited by 206 publications

(144 citation statements)

References 94 publications

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“…Vhlh null growth plates show a dramatic decrease in chondrocyte proliferation at different stages of fetal development, as determined by BrdU labeling. The role of pVHL in regulating cell proliferation is not fully elucidated (Kondo and Kaelin, 2001). Our data differ from previous studies that have shown that lack of functional pVHL impairs cell cycle exit under certain experimental conditions (Bindra et al, 2002;de Paulsen et al, 2001;Pause et al, 1998).…”

Section: Discussioncontrasting

confidence: 99%

Deletion ofVhlhin chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development

et al. 2004

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The von Hippel Lindau tumor suppressor protein (pVHL) is a component of a ubiquitin ligase that promotes proteolysis of the transcription factor hypoxia-inducible-factor 1α (HIF1α), the key molecule in the hypoxic response. We have used conditional inactivation of murine VHL(Vhlh) in all cartilaginous elements to investigate its role in endochondral bone development. Mice lacking Vhlh in cartilage are viable, but grow slower than control littermates and develop a severe dwarfism. Morphologically, Vhlh null growth plates display a significantly reduced chondrocyte proliferation rate, increased extracellular matrix, and presence of atypical large cells within the resting zone. Furthermore, stabilization of the transcription factor HIF1α leads to increased expression levels of HIF1α target genes in Vhlh null growth plates. Lastly, newborns lacking both Vhlh and Hif1agenes in growth plate chondrocytes display essentially the same phenotype as Hif1a null single mutant mice suggesting that the Vhlh null phenotype could result, at least in part, from increased activity of accumulated HIF1α. This is the first study reporting the novel and intriguing findings that pVHL has a crucial role in endochondral bone development and is necessary for normal chondrocyte proliferation in vivo.

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Section: Discussioncontrasting

confidence: 99%

Deletion ofVhlhin chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development

et al. 2004

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“…To date, no direct connections between the functions of hamartin and tuberin and the function of the VHL protein, pVHL, have been identified. pVHL targets the hypoxiainducible transcription factor HIF-1 for degradation, and tumor cells lacking pVHL overproduce HIF target genes, including vascular endothelial growth factor [reviewed in (50)]. pVHL is also believed to play a role in cell cycle regulation and cell differentiation (50).…”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

et al. 2002

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Tuberous sclerosis complex (TSC) is an autosomaldominant disorder characterized by seizures, mental retardation, autism, and tumors of multiple organs. Renal disease in TSC includes angiomyolipomas, cysts, and renal cell carcinomas. It is known that somatic mutations in the von Hippel Lindau (VHL) tumor suppressor gene occur in most clear cell renal carcinomas. To determine whether TSCassociated clear cell carcinomas also contain VHL mutations, we analyzed six tumors for loss of heterozygosity in the VHL gene region of chromosome 3p and for mutations in the VHL gene. Four of the patients were women between the ages of 34 and 68 years, and two were males under the age of 21 years. The loss of heterozygosity analysis was performed using polymorphic microsatellite markers, and the mutational analysis was performed using direct sequencing. Chromosome 3p loss of heterozygosity was not detected, and no VHL mutations were identified. These findings suggest that mutations in the TSC1 and TSC2 genes lead to clear cell renal carcinogenesis via an alternate pathway not involving VHL mutations.

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“…6 Cullins are common subunits of Roc1/Rbx1/Hrt1-Skp1-Cullin/Cdc53-F box (SCF) complexes, which regulate the stability of various proteins involved in cell cycle control and signal transduction. [7][8][9][10] Neddylation of cullins regulates the E3 ubiquitin ligase activity of Roc1/Rbx1/Hrt1-Skp1-Cullin/Cdc53-F box (SCF) complexes. Recent studies have shown that NEDD8 modification facilitates the recruitment of the E2 ubiquitinconjugating enzyme to the SCF complex and mediates the dissociation of p120 CAND1 an inhibitor of SCF ligase activity.…”

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confidence: 99%

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

Kim

et al. 2006

Cell Death Differ

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b-Amyloid precursor protein binding protein 1 (APP-BP1) was previously identified based on its binding to the carboxyl terminal of b-amyloid precursor protein. In this report, we have discovered that a mutation of dAPP-BP1 (Drosophila ortholog of APP-BP1) hinders tissue development, causes apoptosis in imaginal disc cells, and blocks the NEDD8 conjugation pathway. We show that dAPP-BP1 specifically binds the intracellular domain of APP-like protein (APPL). The dAPP-BP1 mutation partially suppresses the abnormal macrochaete phenotype of Appl d , while overexpression of dAPP-BP1 causes abnormal macrochaetes. When APPL is overexpressed, the normal bristle pattern in the fly thorax is disturbed and apoptosis is induced in wing imaginal discs. APPL overexpression phenotypes are enhanced by reducing the level of dAPP-BP1. APPL overexpression is shown to inhibit the NEDD8 conjugation pathway. APPL-induced apoptosis is rescued by overexpression of dAPP-BP1. Our data suggest that APPL and dAPP-BP1 interact antagonistically during Drosophila development.

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The von Hippel–Lindau Tumor Suppressor Gene

Cited by 206 publications

References 94 publications

Deletion ofVhlhin chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development

Deletion ofVhlhin chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

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