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Results: 1 to 8 of 8

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ARNT as a Novel Antifibrotic Target in CKD.
Haase VH
(2019) Am J Kidney Dis 73: 281-284
MeSH Terms: Aryl Hydrocarbon Receptor Nuclear Translocator, Humans, Hypoxia, Kidney Failure, Chronic, Transcription Factors
Added October 28, 2018
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5 MeSH Terms
The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy.
Clark PE
(2009) Kidney Int 76: 939-45
MeSH Terms: Animals, Antibodies, Monoclonal, Antineoplastic Agents, Aryl Hydrocarbon Receptor Nuclear Translocator, Carcinoma, Renal Cell, Drug Design, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Neoplasms, Protein Kinase Inhibitors, Protein Kinases, Receptors, Vascular Endothelial Growth Factor, Signal Transduction, TOR Serine-Threonine Kinases, Translational Medical Research, Treatment Outcome, Vascular Endothelial Growth Factor A, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added May 27, 2014
The basic biology underlying the development of clear-cell renal cell carcinoma (ccRCC) is critically dependent on the von Hippel-Lindau gene (VHL), whose protein product is important in the cell's normal response to hypoxia. Aberrations in VHL's function, either through mutation or promoter hypermethylation, lead to accumulation of the transcriptional regulatory molecule, hypoxia-inducible factor alpha (HIFalpha). HIFalpha can then dimerize with HIFbeta and translocate to the nucleus, where it will transcriptionally upregulate a series of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others. Binding of these ligands to their cognate receptors activates a series of kinase- dependent signaling pathways, including the RAF-MEK-ERK and phosphatidylinositol-3 kinase-AKT-mTOR pathways. Targeted agents developed and now approved for use in advanced ccRCC include humanized monoclonal antibodies against VEGF, small-molecule tyrosine kinase inhibitors, and inhibitors of mTOR. Understanding the biology of ccRCC is critical in understanding the current therapy for the disease and in developing novel therapeutics in the future. This review will provide an overview of the genetics of ccRCC, with an emphasis on how this has informed the development of the targeted therapeutics for this disease.
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19 MeSH Terms
Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade.
Shah YM, Ito S, Morimura K, Chen C, Yim SH, Haase VH, Gonzalez FJ
(2008) Gastroenterology 134: 2036-48, 2048.e1-3
MeSH Terms: Animals, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Transcription Factors, Colitis, Colon, Dextran Sulfate, Disease Models, Animal, Enzyme Inhibitors, Gene Expression Regulation, Hypoxia-Inducible Factor 1, alpha Subunit, Inflammation Mediators, Integrases, Intestinal Mucosa, Intramolecular Oxidoreductases, Isoxazoles, Macrophage Migration-Inhibitory Factors, Mice, Mice, Transgenic, Recombination, Genetic, Signal Transduction, Time Factors, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added August 19, 2013
BACKGROUND & AIMS - Colon epithelial cells are critical for barrier function and contain a highly developed immune response. A previous study has shown hypoxia-inducible factor (HIF) as a critical regulator of barrier protection during colon epithelial injury. However, the role of HIF signaling in colon mucosal immunity is not known.
METHODS - With the use of cre/loxP technology, intestinal-specific disruption of von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (Hif)-1alpha, and aryl hydrocarbon nuclear translocator (Arnt) was generated. Colon inflammation was induced using a dextran sulfate sodium (DSS)-induced colitis model, and the mice were analyzed by histologic analysis, Western blot analysis, and quantitative polymerase chain reaction.
RESULTS - In mice, colonic epithelium disruption of Vhl resulted in constitutive expression of HIF, which initiated an increase in inflammatory infiltrates and edema in the colon. These effects were ameliorated in mice by disruption of both Vhl and Arnt/Hif1beta (which inactivates HIF). In a DSS-induced colitis model, increased HIF expression correlated with more severe clinical symptoms and an increase in histologic damage, while disruption of both Vhl and Arnt in the colon epithelium inhibited these effects. Furthermore, colons with constitutive activation of HIF displayed increased expression of proinflammatory mediators that were synergistically potentiated following DSS administration and reduced by inhibition of the proinflammatory and direct HIF target gene macrophage migration inhibitory factor.
CONCLUSIONS - The present study shows that a chronic increase in HIF signaling in the colon epithelial cells initiates a hyperinflammatory reaction that may have important implications in developing therapeutic strategies for inflammatory bowel disease.
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22 MeSH Terms
Hypoxia-inducible factor-1 inhibition in combination with temozolomide treatment exhibits robust antitumor efficacy in vivo.
Li L, Lin X, Shoemaker AR, Albert DH, Fesik SW, Shen Y
(2006) Clin Cancer Res 12: 4747-54
MeSH Terms: Administration, Oral, Angiogenesis Inhibitors, Animals, Antineoplastic Agents, Aryl Hydrocarbon Receptor Nuclear Translocator, Caspases, Cell Death, Cell Line, Tumor, Cell Proliferation, Dacarbazine, Disease Models, Animal, Dose-Response Relationship, Drug, Glucose, Humans, Hypoxia, Indazoles, Mice, Mice, SCID, Phenylurea Compounds, Structure-Activity Relationship, Temozolomide, Transplantation, Heterologous, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
PURPOSE - Inhibiting hypoxia-inducible factor-1 (HIF-1) represents a unique mechanism for cancer therapy. It is conceived that HIF-1 inhibitors may synergize with many classes of cancer therapeutic agents, such as angiogenesis inhibitors and cytotoxic drugs, to achieve a more robust tumor response. However, these hypotheses have not been rigorously tested in tumor models in vivo. The present study was carried out to evaluate the antitumor efficacy of combining HIF-1 inhibition with angiogenesis inhibitors or cytotoxic agents.
EXPERIMENTAL DESIGN - Using a D54MG-derived tumor model that allows knockdown of HIF-1alpha on doxycycline treatment, we examined the tumor responses to chemotherapeutic agents, including the angiogenesis inhibitor ABT-869 and cytotoxic agents 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide, in the presence or absence of an intact HIF-1 pathway.
RESULTS - Surprisingly, inhibiting HIF-1 in tumors treated with the angiogenesis inhibitor ABT-869 did not produce much added benefit compared with ABT-869 treatment alone, suggesting that the combination of an angiogenesis inhibitor with a HIF-1 inhibitor may not be a robust therapeutic regimen. In contrast, the cytotoxic drug temozolomide, when used in combination with HIF-1alpha knockdown, exhibited a superadditive and likely synergistic therapeutic effect compared with the monotherapy of either treatment alone in the D54MG glioma model.
CONCLUSIONS - Our results show that the DNA alkylating agent temozolomide exhibits robust antitumor efficacy when used in combination with HIF-1 inhibition in D54MG-derived tumors, suggesting that the combination of temozolomide with HIF-1 inhibitors might be an effective regimen for cancer therapy. In addition, our results also show that the RNA interference-based inducible knockdown model can be a valuable platform for further evaluation of the combination treatment of other cancer therapeutics with HIF-1 inhibition.
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23 MeSH Terms
Hypoxia-inducible factors in the kidney.
Haase VH
(2006) Am J Physiol Renal Physiol 291: F271-81
MeSH Terms: Animals, Apoptosis, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Transcription Factors, Disease Models, Animal, Erythropoiesis, Gene Expression Regulation, Gene Expression Regulation, Developmental, Gene Expression Regulation, Neoplastic, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Kidney Neoplasms, Mice, Signal Transduction
Show Abstract · Added August 19, 2013
Tissue hypoxia not only occurs under pathological conditions but is also an important microenvironmental factor that is critical for normal embryonic development. Hypoxia-inducible factors HIF-1 and HIF-2 are oxygen-sensitive basic helix-loop-helix transcription factors, which regulate biological processes that facilitate both oxygen delivery and cellular adaptation to oxygen deprivation. HIFs consist of an oxygen-sensitive alpha-subunit, HIF-alpha, and a constitutively expressed beta-subunit, HIF-beta, and regulate the expression of genes that are involved in energy metabolism, angiogenesis, erythropoiesis and iron metabolism, cell proliferation, apoptosis, and other biological processes. Under conditions of normal Po(2), HIF-alpha is hydroxylated and targeted for rapid proteasomal degradation by the von Hippel-Lindau (VHL) E3-ubiquitin ligase. When cells experience hypoxia, HIF-alpha is stabilized and either dimerizes with HIF-beta in the nucleus to form transcriptionally active HIF, executing the canonical hypoxia response, or it physically interacts with unrelated proteins, thereby enabling convergence of HIF oxygen sensing with other signaling pathways. In the normal, fully developed kidney, HIF-1alpha is expressed in most cell types, whereas HIF-2alpha is mainly found in renal interstitial fibroblast-like cells and endothelial cells. This review summarizes some of the most recent advances in the HIF field and discusses their relevance to renal development, normal kidney function and disease.
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16 MeSH Terms
Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor.
Rankin EB, Tomaszewski JE, Haase VH
(2006) Cancer Res 66: 2576-83
MeSH Terms: Animals, Aryl Hydrocarbon Receptor Nuclear Translocator, Gene Silencing, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Diseases, Cystic, Kidney Tubules, Proximal, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nephrons, Phosphoenolpyruvate Carboxylase, Promoter Regions, Genetic, Rats, Recombinases, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease
Show Abstract · Added September 9, 2013
Inactivation of the von Hippel-Lindau tumor suppressor, pVHL, is associated with both hereditary and sporadic renal cysts and renal cell carcinoma, which are commonly thought to arise from the renal proximal tubule. pVHL regulates the protein stability of hypoxia-inducible factor (HIF)-alpha subunits and loss of pVHL function leads to HIF stabilization. The role of HIF in the development of VHL-associated renal lesions remains to be determined. 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. We found that conditional inactivation of VHL in PEPCK-Cre mutants resulted in renal cyst development that was associated with increased erythropoietin levels and polycythemia. Increased expression of the HIF target gene erythropoietin was limited to the liver, whereas expression of carbonic anhydrase 9 and multidrug resistance gene 1 was up-regulated in the renal cortex of mutant mice. Inactivation of the HIF-alpha binding partner, arylhydrocarbon receptor nuclear translocator (Arnt), but not Hif-1alpha, suppressed the development of renal cysts. Here, we present the first mouse model of VHL-associated renal disease that will provide a basis for further genetic studies to define the molecular events that are required for the progression of VHL-associated renal cysts to clear cell renal cell carcinoma.
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18 MeSH Terms
VHL: oxygen sensing and vasculogenesis.
Rathmell WK, Simon MC
(2005) J Thromb Haemost 3: 2627-32
MeSH Terms: Aryl Hydrocarbon Receptor Nuclear Translocator, Blood Vessels, Hematopoiesis, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Oxygen, von Hippel-Lindau Disease
Added October 17, 2015
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8 MeSH Terms
Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice.
Rankin EB, Higgins DF, Walisser JA, Johnson RS, Bradfield CA, Haase VH
(2005) Mol Cell Biol 25: 3163-72
MeSH Terms: Animals, Aryl Hydrocarbon Receptor Nuclear Translocator, DNA-Binding Proteins, Erythropoietin, Gene Deletion, Gene Expression, Gene Silencing, Genes, Tumor Suppressor, Hemangioma, Cavernous, Hepatocytes, Hypoxia-Inducible Factor 1, alpha Subunit, Liver, Liver Neoplasms, Mice, Mice, Knockout, Phosphotransferases (Alcohol Group Acceptor), Polycythemia, Receptors, Aryl Hydrocarbon, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Vascular Endothelial Growth Factor A, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease
Show Abstract · Added August 19, 2013
Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. 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. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1alpha (Hif-1alpha) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1alpha did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.
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24 MeSH Terms