Disease relevance of Vhlh

• Mice lacking Vhlh in cartilage are viable, but grow slower than control littermates and develop a severe dwarfism [1].
• Surprisingly, growth of both Vhl(-)(/)(-) MEFs and fibrosarcomas was impaired, although tumor vascularity was increased [2].
• Cloning and characterization of a mouse gene with homology to the human von Hippel-Lindau disease tumor suppressor gene: implications for the potential organization of the human von Hippel-Lindau disease gene [3].
• Whereas no spontaneous lung tumors were observed in Fhit-/- or Vhl+/- mice, 44% of Fhit-/-Vhl+/- mice developed adenocarcinomas by 2 years of age [4].
• Loss of pVHL leads to the development of sporadic renal cell carcinomas (RCCs) [5].

High impact information on Vhlh

• Using green fluorescent protein-tagged end-binding protein 1 to label microtubule plus ends, we found that pVHL does not affect the microtubule growth rate but is needed to orient the growth of microtubules toward the cell periphery, a prerequisite for the formation of cilia [6].
• Knockdown of pVHL impeded the formation of cilia in mouse inner medullary collecting duct 3 kidney cells, whereas the expression of pVHL in VHL-negative renal cancer cells rescued the ciliogenesis defect [6].
• We found that the impaired migration and adhesion of VHL-null endothelial cells can be partially rescued by the addition of back exogenous fibronectin, which indicates that pVHL regulation of fibronectin deposition plays an important functional role in vascular patterning and maintenance of vascular integrity [7].
• pVHL function is essential for endothelial extracellular matrix deposition [7].
• Priming-dependent phosphorylation and regulation of the tumor suppressor pVHL by glycogen synthase kinase 3 [8].

Chemical compound and disease context of Vhlh

• Wild-type mice developed a low-frequency of liver angiectasis (7-15%) only at the highest doses of carcinogen used (150 and 200 mg/kg, respectively) while Vhl+/- mice exhibited angiectasis, hemangioma and hemangiosarcomas with a frequency ranging from 19 to 46% at 50-200 mg/kg streptozotocin [9].

Biological context of Vhlh

• Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes [10].
• Thymi from Vhlh-deficient mice were small due to a severe reduction in the total number of CD4/CD8-double-positive thymocytes which was associated with increased apoptosis in vivo and in vitro [10].
• Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development [1].
• We have used conditional inactivation of murine VHL (Vhlh) in all cartilaginous elements to investigate its role in endochondral bone development [1].
• Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined [11].

Anatomical context of Vhlh

• In order to investigate the role of pVhl in T-cell development, we generated mice with thymocyte-specific inactivation of Vhlh resulting in constitutive transcriptional activity of Hif-1, as well as mice with thymocyte-specific repression of Hif-1 in a wild-type and Vhlh-deficient background [10].
• Furthermore, stabilization of the transcription factor HIF1alpha leads to increased expression levels of HIF1alpha target genes in Vhlh null growth plates [1].
• 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 [1].
• To investigate the role of Vhl in cellular proliferation and tumorigenesis, we utilized mouse embryonic fibroblasts (MEFs), a common tool for analyzing cell cycle regulation, and generated Vhl(-)(/)(-) MEF-derived fibrosarcomas [2].
• To investigate the functional consequences of pVHL inactivation and the role of HIF signaling in renal epithelial cells, we used the phosphoenolpyruvate carboxykinase (PEPCK) promoter to generate transgenic mice in which Cre-recombinase is expressed in the renal proximal tubule and in hepatocytes [12].

Associations of Vhlh with chemical compounds

• Surprisingly, HIF1alpha and HIF2alpha were induced during TS cell differentiation in 20% O2; additionally, pVHL levels were modulated during the same time period [13].
• No differences were observed between wild-type and Vhl+/- animals in the frequency or type of renal lesions induced by 50-200 mg/kg streptozotocin [9].

Physical interactions of Vhlh

• It is concluded that seal HIF-1alpha may act as a transcriptional activator and that its presence in seal tissues is probably not caused by its inability to interact with pVHL [14].

Other interactions of Vhlh

• During the course of nephrotoxicity, levels of pVHL, a factor that destabilizes HIF-1 alpha, increased significantly [15].
• Decreased proliferation of Vhl(-)(/)(-) MEFs was correlated with an overexpression of cyclin kinase inhibitors (CKIs) p21 and p27 [2].
• The induction of p21 and p27, mediated by constitutive activation of the HIF pathway, provides a mechanism for the decreased proliferation rates of Vhl(-)(/)(-) MEFs and fibrosarcomas [2].

Analytical, diagnostic and therapeutic context of Vhlh

• Cell type specific gene targeting of VHL in mice has demonstrated that proper pVHL mediated HIF proteolysis is fundamentally important for survival, proliferation and differentiation of many cell types and furthermore, that inactivation of pVHL may, unexpectedly, inhibit tumor growth under certain conditions [16].
• Using fluorescence in situ hybridization, we localized the rat homolog of the von Hippel-Lindau gene (Vhl) to rat chromosome band 4q41.3-->q42 [17].

References