Disruption of tubular Flcn expression as a mouse model for renal tumor induction.

The study of kidney cancer pathogenesis and its treatment has been limited by the scarcity of genetically defined animal models. The FLCN gene that codes for the protein folliculin, mutated in Birt-Hogg-Dubé syndrome, presents a new target for mouse modeling of kidney cancer. Here we developed a kidney-specific knockout model by disrupting the mouse Flcn in the proximal tubules, thus avoiding homozygous embryonic lethality or neonatal mortality, and eliminating the requirement of loss of heterozygosity for tumorigenesis.

A novel MET-interacting protein shares high sequence similarity with RanBPM, but fails to stimulate MET-induced Ras/Erk signaling.

MET is a receptor protein tyrosine kinase for hepatocyte growth factor, a multifunctional cytokine controlling cell growth, morphogenesis, and motility. In our previous study, RanBPM/RanBP9, whose name originated from its ability to interact with Ran, was identified as a MET-interacting protein. RanBPM/RanBP9 activates the Ras/Erk signaling pathway by serving as an adaptor protein of MET to recruit Sos.

Identification of the RNA polymerase II subunit hsRPB7 as a novel target of the von Hippel-Lindau protein.

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is linked to the hereditary VHL disease and sporadic clear cell renal cell carcinomas (CCRCC). VHL-associated tumors are highly vascularized, a characteristic associated with overproduction of vascular endothelial growth factor (VEGF). The VHL protein (pVHL) is a component of the ubiquitin ligase E3 complex, targeting substrate proteins for ubiquitylation and subsequent proteasomic degradation.

Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas.

Unlabelled: PURPOSE The von Hippel-Lindau (VHL) tumor suppressor gene is frequently inactivated in the common type of sporadic clear cell renal cell carcinoma (RCC) as well as RCCs associated with VHL disease. The VHL protein targets hypoxia-inducible factor-1 alpha (HIF-1 alpha), a transcription factor that can induce vascular endothelial growth factor (VEGF) expression, for ubiquitination and degradation. Accumulation of HIF-1 alpha caused by mutant VHL protein in tumor cells may result in VEGF over expression, which has been used to explain the increased vascularity of RCC.

The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity.

The von Hippel-Lindau tumor suppressor (pVHL) is a component of an E3 ubiquitin ligase and targets hypoxia-inducible factor-1alpha (HIF-1alpha) for ubiquitylation and degradation under normoxic conditions. pVHL also directly inhibits HIF-1alpha transactivation by recruiting histone deacetylases. Here, we report a novel pVHL-interacting protein that functions as a negative regulator of HIF-1alpha transactivation.

Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor.

The VHL protein (pVHL) is a component of an E3 ubiquitin ligase complex which is involved in the ubiquitination and degradation of the alpha subunits of HIF (hypoxia-inducible factor) in the presence of oxygen. However, it is of considerable interest to identify pVHL substrates other than HIF. In our previous studies, we have shown that VDU1 (pVHL-interacting deubiquitinating enzyme-1) can be ubiquitinated for rapid degradation in a pVHL-dependent manner.

Clinical association with urinary glycosaminoglycans and urolithiasis.

Objectives: To determine the clinical association between urinary glycosaminoglycan (GAG) concentration and kidney stone disease.

Methods: Thirty-five patients (14 women and 21 men) with a history of stone disease and 37 controls (13 women and 24 men) were evaluated for urinary GAG concentration. By using a new dye-binding assay, the total GAG concentration in the urine was measured and corrected to urinary creatinine levels (micrograms of GAG per milligram creatinine).

Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations of the VHL gene. Recent studies suggest that VHL protein (pVHL) is a component of an E3 ubiquitin ligase, but the detailed biological function of pVHL remains to be determined. To further elucidate the biological functions of pVHL, we searched pVHL-interacting proteins using yeast two-hybrid screening.