Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

von Hippel-Lindau (VHL) disease is caused by loss of function of the VHL tumor suppressor protein. Here, we demonstrate that the folding and assembly of VHL into a complex with its partner proteins, elongin B and elongin C (herein, elongin BC), is directly mediated by the chaperonin TRiC/CCT. Association of VHL with TRiC is required for formation of the VHL-elongin BC complex. A 55-amino acid domain of VHL is both necessary and sufficient for binding to TRiC. Importantly, mutation or deletion of this domain is associated with VHL disease. We identified two mutations that disrupt the normal interaction with TRiC and impair VHL folding. Our results define a novel role for TRiC in mediating oligomerization and suggest that inactivating mutations can impair polypeptide function by interfering with chaperone-mediated folding.
Mol Cell 1999 Dec
PMID:Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC. 1063 29

Oxygen is crucial to aerobic metabolism, but excesses of oxygen or reactive oxygen species (ROS) can injure cells. This minireview addresses two transcription factors that regulate several cellular responses to oxygen tension. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric protein activated by hypoxia. Levels of HIF-1 are regulated by removal of the HIF-1alpha subunit through ubiquination and proteasomal destruction under normoxic conditions. Hypoxia inhibits the ubiquination of HIF-1alpha, preventing its destruction and allowing it to bind to hypoxia-responsive elements in gene promoter, enhancer, and intronic sequences. HIF-1 induces the expression of the hypoxia responsive genes vascular endothelial growth factor and erythropoietin. Its dysregulation has been implicated in von Hippel-Lindau disease. Nuclear factor kappaB (NFkappaB) is a family of pleotropic, dimeric transcription factors, and has a complex pattern of regulation. Under normoxic conditions, NFkappaB is bound to one of several inhibitory proteins (e.g., IkappaB) that prevent its nuclear translocation. Hyperoxia or elevations of ROS cause the ubiquination and destruction of the inhibitory proteins, freeing NFkappaB and allowing it to bind to target gene promoters. Hyperoxia in cell and animal models and acute lung injury in humans induce the expression of multiple proinflammatory cytokines through NFkappaB-dependent mechanisms. Although HIF-1 and NFkappaB respond to changes in pO(2), the precise nature of the oxygen sensing and transduction pathways is unclear in both cases. Both heme-protein and redox-sensitive mechanisms have been proposed. Improved understanding of oxygen-sensitive gene regulation may suggest targeted therapies for human disease.
Mol Genet Metab
PMID:Oxygen regulation of gene expression: a study in opposites. 1100 29

Mutations in the von Hippel-Lindau (VHL) gene are involved in the family cancer syndrome for which it is named and the development of sporadic renal cell cancer (RCC). Reintroduction of VHL into RCC cells lacking functional VHL [VHL(-)] can suppress their growth in nude mice, but not under standard tissue culture conditions. To examine the hypothesis that the tumor suppressor function of VHL requires signaling through contact with extracellular matrix (ECM), 786-O VHL(-) RCC cells and isogenic sublines stably expressing VHL gene products [VHL(+)] were grown on ECMs. Cell-cell and cell-ECM signalings were required to elicit VHL-dependent differences in growth and differentiation. VHL(+) cells differentiated into organized epithelial sheets, whereas VHL(-) cells were branched and disorganized. VHL(+) cells grown to high density on collagen I underwent growth arrest, whereas VHL(-) cells continued to proliferate. Integrin levels were up-regulated in VHL(-) cells, and cell adhesion was down-regulated in VHL(+) cells during growth at high cell density. Hepatocyte nuclear factor 1alpha, a transcription factor and global activator of proximal tubule-specific genes in the nephron, was markedly up-regulated in VHL(+) cells grown at high cell density. These data indicate that VHL can induce renal cell differentiation and mediate growth arrest through integration of cell-cell and cell-ECM signals.
Mol Cell Biol 2001 Feb
PMID:VHL induces renal cell differentiation and growth arrest through integration of cell-cell and cell-extracellular matrix signaling. 1115 73

The von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene on human chromosome 3p25. It is characterized clinically by vascular tumors including benign hemangioblastomas of the cerebellum, spine, brain stem and retina. Clear-cell renal cell carcinoma is a frequent cause of death, occurring in up to 70% of patients with VHL. Pheochromocytomas occur in association with specific alleles (usually mutations as opposed to deletions), therefore a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members. The VHL gene coding sequence contains three exons. Two isoforms of mRNA exist, reflecting the presence or absence of exon 2. Tumors arise following the loss or inactivation of the wild-type allele in a cell. In initial studies approximately 20% of patients had large germline mutations detectable by Southern blot analysis, 27% had missense mutations and 27% had nonsense or frameshift mutations. Advances in mutation analysis now allow for a 100% mutation detection rate in families with definite VHL. Families may be characterized by the presence [type 2 (7-20% of families)] or absence (type 1) of pheochromocytomas. Most type 2 families are affected by missense mutations, whereas most type 1 families have deletions or premature termination mutations. The prognosis for the lifetime risk of pheochromocytoma can be estimated by determination of the underlying mutation even if there is no family history of VHL.
Hum Mol Genet 2001 Apr
PMID:Genotype-phenotype correlation in von Hippel-Lindau syndrome. 1125 10

Endothelial cells (EC) infected with the VHL strain of cytomegalovirus (CMV) are resistant to p53-mediated apoptosis, which may be relevant to EC dysfunction and atherogenesis. This resistance to apoptosis may be mediated by cytoplasmic sequestration of p53, which functions only in the nucleus. We explored the hypothesis that CMV sequesters p53 in the cytoplasm by blocking p53 nuclear localization signal (NLS) function. We transfected VHL CMV infected EC with recombinant p53 NLSI conjugated with chicken muscle pyruvate kinase (PK) plasmid. NLSI is responsible for 90% of p53 nuclear localization, and PK is not normally translocated to the nucleus after cytoplasmic production. Thus it cannot be localized in the nucleus without the assistance of the artificial NLSI. A double-labeling immunofluorescence staining method was used to identify the localization of p53 NLSI-conjugated PK in CMV-infected EC. We found that CMV infection sequesters PK and p53 in the cytoplasm by blocking NLSI function. This inactivation of NLSI function is dependent upon infection stage; it occurs only in the early and late phases and not the immediate early phase of infection. These findings may be relevant to endothelial dysfunction and initiation of atherogenesis. Our study also suggests a novel mechanism of the p53 inactivation by virus, which may be important for atherogenesis and tumorgenesis.
J Mol Med (Berl) 2001
PMID:Cytomegalovirus inhibits p53 nuclear localization signal function. 1126 11

Loss of heterozygosity (LOH) on chromosome 3p is a common event in cervical cancer and typically occurs in a dispersed pattern involving several loci. This implies that more than one resident tumor-suppressor gene is involved in the genesis of these tumors; however, specific targets remain to be identified. The region of 3p14.2-pter encompasses a region of frequent loss and contains at least three tumor-suppressor genes: fragile histidine triad (FHIT), transforming growth factor-beta receptor II (T beta R-II), and Von Hippel-Lindau. To identify those loci within 3p14.2-pter that are important in cervical cancer, invasive tumors were first subjected to high-density LOH analysis. With 25 microsatellite markers, LOH was detected in seven of 15 cervical carcinomas (47%). Losses always included markers mapping to 3p22, and markers at this location were exclusively lost in two tumors, implicating this as a site of a cervical tumor-suppressor gene. Because it is a known tumor-suppressor gene located at 3p22 and thus a potential target for inactivation in these tumors, the T beta R-II gene was subsequently screened for mutation and altered expression levels. Whereas no tumor-derived mutations were detected in any of the tumors, six of ten tumors showed T beta R-II transcript levels reduced by > or = 50% when compared with normal cervical epithelium. Nine of 15 (60%) tumors exhibited LOH at 3p22 or reduced expression of T beta R-II, suggesting that reduced T beta R-II levels contribute to cervical tumorigenesis. Two cases exhibited silent germline polymorphisms of T beta R-II: one corresponding to a C1167T transversion and the other to an A1266G transition. The FHIT gene, which is located at 3p14.2, also frequently incurred LOH and abnormal transcription in these tumors. LOH of FHIT was observed in five of the 15 tumors analyzed. Neither mutations nor homozygous deletions of FHIT were detected in the tumors. However, aberrantly short transcripts of the FHIT gene were evident in six of nine (67%) tumors. Only one of these also displayed LOH, indicating that this gene was altered in at least 10 of 15 (67%) tumors. These results provide evidence that the inactivation of two known tumor-suppressor genes, TbetaR-II and FHIT, on chromosome 3p is involved in cervical carcinogenesis. Mol. Carcinog. 30:159--168, 2001.
Mol Carcinog 2001 Mar
PMID:Chromosome 3p tumor-suppressor gene alterations in cervical carcinomas. 1130 76

The theory of stochastic transcription termination based on free-energy competition [von Hippel, P. H. & Yager, T. D. (1992) Science 255, 809-812 and von Hippel, P. H. & Yager, T. D. (1991) Proc. Natl. Acad. Sci. USA 88, 2307-2311] requires two or more reaction rates to be delicately balanced over a wide range of physical conditions. A large body of work on glasses and large molecules suggests that this balancing should be impossible in such a large system in the absence of a new organizing principle of matter. We review the experimental literature of termination and find no evidence for such a principle, but do find many troubling inconsistencies, most notably, anomalous memory effects. These effects suggest that termination has a deterministic component and may conceivably not be stochastic at all. We find that a key experiment by Wilson and von Hippel [Wilson, K. S. & von Hippel, P. H. (1994) J. Mol. Biol. 244, 36-51] thought to demonstrate stochastic termination was an incorrectly analyzed regulatory effect of Mg(2+) binding.
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PMID:Balanced branching in transcription termination. 1130 13

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germ line mutation of the von Hippel-Lindau tumor suppressor gene (VHL). Tumors observed in this disorder include retinal and central nervous system hemangioblastomas, clear cell renal carcinomas and pheochromocytomas. The VHL gene product, pVHL, is a component of a ubiquitin ligase which targets the transcription factor known as hypoxia-inducible factor (HIF) for degradation in the presence of oxygen. pVHL also plays roles in the control of extracellular matrix formation and cell-cycle exit. Different VHL mutations confer different site-specific risks of cancer. Type 2C VHL mutations confer an increased risk of pheochromocytoma without the other stigmata of VHL disease. Here we report that the products of such type 2C VHL alleles retain the ability to down regulate HIF but are defective for promotion of fibronectin matrix assembly. Furthermore, pVHL L188V, a well studied type 2C mutant, retained the ability to suppress renal carcinoma growth in vivo. These studies strengthen the notion that HIF deregulation plays a causal role in hemangioblastoma and renal carcinoma, and raises the possibility that abnormal fibronectin matrix assembly contributes to pheochromocytoma pathogenesis in the setting of VHL disease.
Hum Mol Genet 2001 May 01
PMID:von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. 1133 12

The von Hippel-Lindau tumour suppressor gene product (pVHL) associates with the elongin B and C and Cul2 proteins to form a ubiquitin-ligase complex (VCBC). To date, the only VCBC substrates identified are the hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha). However, pVHL is thought to have multiple functions and the significance of HIF-1alpha and HIF-2alpha regulation for tumour suppressor activity has not been defined. VHL disease is characterized by distinct clinical subtypes. Thus haemangioblastomas (HABs) and renal cell carcinoma (RCC) but not phaeochromocytoma (PHE) occur in type 1 VHL disease. Type 2 subtypes are characterized by PHE susceptibility but differ with respect to additional tumours (type 2A, PHE+HAB but not RCC; type 2B, PHE+ HAB+RCC; type 2C, PHE only). We investigated in detail the effect of 13 naturally occurring VHL mutations (11 missense), representing each phenotypic subclass, on HIF-alpha subunit regulation. Consistent effects on pVHL function were observed for all mutations within each subclass. Mutations associated with the PHE-only phenotype (type 2C) promoted HIF-alpha ubiquitylation in vitro and demonstrated wild-type binding patterns with pVHL interacting proteins, suggesting that loss of other pVHL functions are necessary for PHE susceptibility. Mutations causing HAB susceptibility (types 1, 2A and 2B) demonstrated variable effects on HIF-alpha subunit and elongin binding, but all resulted in defective HIF-alpha regulation and loss of p220 (fibronectin) binding. All RCC-associated mutations caused complete HIF-alpha dysregulation and loss of p220 (fibronectin) binding. Our findings are consistent with impaired ability to degrade HIF-alpha subunit being required for HAB development and RCC susceptibility.
Hum Mol Genet 2001 May 01
PMID:Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. 1133 13

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1alpha and HIF-1beta subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1alpha expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1alpha for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1alpha. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1alpha expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1alpha but instead stimulates HIF-1alpha synthesis in a rapamycin-dependent manner. The 5'-untranslated region of HIF-1alpha mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1alpha expression.
Mol Cell Biol 2001 Jun
PMID:HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. 1135 7


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