Gene Symbol: Vhl
Description: von Hippel-Lindau tumor suppressor
Alias: Vhlh, von Hippel-Lindau disease tumor suppressor, pVHL, von Hippel-Lindau syndrome homolog, von Hippel-Lindau syndrome protein homolog
Species: mouse
Products:     Vhl

Top Publications

  1. Rankin E, Higgins D, Walisser J, Johnson R, Bradfield C, Haase V. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol Cell Biol. 2005;25:3163-72 pubmed
    ..Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to ..
  2. Wan C, Gilbert S, Wang Y, Cao X, Shen X, Ramaswamy G, et al. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci U S A. 2008;105:686-91 pubmed publisher
    ..Mice lacking pVHL in osteoblasts with constitutive HIF-1alpha activation in osteoblasts had markedly increased vascularity and ..
  3. Rankin E, Rha J, Unger T, Wu C, Shutt H, Johnson R, et al. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene. 2008;27:5354-8 pubmed publisher
    The von Hippel-Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factors (HIF)-1 and -2, oxygen-sensitive basic helix-loop-helix transcription factors, which mediate the hypoxic induction of angiogenic growth ..
  4. Lee C, Hickey M, Sanford C, McGuire C, Cowey C, Simon M, et al. VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene. 2009;28:1694-705 pubmed publisher
    ..Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-alpha regulation...
  5. Chen S, Sanford C, Sun J, Choi V, van Dyke T, Samulski R, et al. VHL and PTEN loss coordinate to promote mouse liver vascular lesions. Angiogenesis. 2010;13:59-69 pubmed publisher
    Von Hippel-Lindau (VHL) inactivation develops a tumor syndrome characterized by highly vascularized tumors as a result of hypoxia inducible factors (HIF) stabilization...
  6. Lange C, Heynen S, Tanimoto N, Thiersch M, Le Y, Meneau I, et al. Normoxic activation of hypoxia-inducible factors in photoreceptors provides transient protection against light-induced retinal degeneration. Invest Ophthalmol Vis Sci. 2011;52:5872-80 pubmed publisher
    ..Rod-specific Vhl knockdown mice were generated using the Cre-lox system with the rod opsin promoter controlling expression of CRE ..
  7. Kim W, Safran M, Buckley M, Ebert B, Glickman J, Bosenberg M, et al. Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J. 2006;25:4650-62 pubmed
    Many functions have been assigned to the von Hippel-Lindau tumor suppressor gene product (pVHL), including targeting the alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction...
  8. Kimura K, Iwano M, Higgins D, Yamaguchi Y, Nakatani K, Harada K, et al. Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol. 2008;295:F1023-9 pubmed publisher
    ..we generated a knockout mouse in which tubular epithelial expression of von Hippel-Lindau tumor suppressor (VHL), which acts as a ubiquitin ligase to promote proteolysis of HIF-1alpha, was targeted...
  9. Weidemann A, Krohne T, Aguilar E, Kurihara T, Takeda N, Dorrell M, et al. Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia. 2010;58:1177-85 pubmed publisher
    ..factors HIF-1 alpha and HIF-2 alpha, and the negative regulator of HIF alpha, von Hippel-Lindau protein (VHL), in astrocytes...

More Information


  1. Kapitsinou P, Liu Q, Unger T, Rha J, Davidoff O, Keith B, et al. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood. 2010;116:3039-48 pubmed publisher
    ..Furthermore, we provide evidence that hepatocyte-derived Hif-2 is involved in the regulation of iron metabolism genes, supporting a role for HIF-2 in the coordination of EPO synthesis with iron homeostasis. ..
  2. Haase V, Glickman J, Socolovsky M, Jaenisch R. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A. 2001;98:1583-8 pubmed
    von Hippel-Lindau (VHL) disease is a pleomorphic familial tumor syndrome that is characterized by the development of highly vascularized tumors. Homozygous disruption of the VHL gene in mice results in embryonic lethality...
  3. Ma W, Tessarollo L, Hong S, Baba M, Southon E, Back T, et al. Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. Cancer Res. 2003;63:5320-8 pubmed
    ..Loss of pVHL function in this VHL conditional knockout mouse model results in an extensive abnormal vascular phenotype in ..
  4. Hong S, Furihata M, Baba M, Zbar B, Schmidt L. Vascular defects and liver damage by the acute inactivation of the VHL gene during mouse embryogenesis. Lab Invest. 2006;86:664-75 pubmed
    Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene leads to the development of central nervous system hemangioblastomas, pheochromocytomas and renal cell carcinomas...
  5. Tang N, Mack F, Haase V, Simon M, Johnson R. pVHL function is essential for endothelial extracellular matrix deposition. Mol Cell Biol. 2006;26:2519-30 pubmed
    The tumor suppressor von Hippel-Lindau protein (pVHL) is critical for cellular molecular oxygen sensing, acting to target degradation of the hypoxia-inducible factor alpha transcription factor subunits under normoxic conditions...
  6. Theilig F, Enke A, Scolari B, Polzin D, Bachmann S, Koesters R. Tubular deficiency of von Hippel-Lindau attenuates renal disease progression in anti-GBM glomerulonephritis. Am J Pathol. 2011;179:2177-88 pubmed publisher
    ..of HIF on tubulointerstitial disease development in primary glomerular disease, transgenic von Hippel Lindau (VHL)-knockout mice were generated and null expression was induced before the onset of autoimmune IgG-mediated anti-..
  7. Zanesi N, Mancini R, Sevignani C, Vecchione A, Kaou M, Valtieri M, et al. Lung cancer susceptibility in Fhit-deficient mice is increased by Vhl haploinsufficiency. Cancer Res. 2005;65:6576-82 pubmed
    ..frequency of tumor induction, we examined the spontaneous and dimethylnitrosamine-induced tumor phenotype of Fhit-/-Vhl+/- mice...
  8. Frew I, Thoma C, Georgiev S, Minola A, Hitz M, Montani M, et al. pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J. 2008;27:1747-57 pubmed publisher
    ..Strikingly, combined conditional inactivation of Vhlh and the Pten tumour suppressor gene, which normally antagonises PI3K signalling, in the mouse kidney, elicits cyst ..
  9. Young A, Schlisio S, Minamishima Y, Zhang Q, Li L, Grisanzio C, et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol. 2008;10:361-9 pubmed publisher
    Germline von Hippel-Lindau tumour suppressor gene (VHL) mutations cause renal cell carcinomas, haemangioblastomas and phaeochromocytomas in humans. Mutations in VHL also occur in sporadic renal cell carcinomas...
  10. Schermer B, Ghenoiu C, Bartram M, Muller R, Kotsis F, Höhne M, et al. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J Cell Biol. 2006;175:547-54 pubmed
    ..In this study, we demonstrate that the von Hippel-Lindau (VHL) protein (pVHL) is a ciliary protein that controls ciliogenesis in kidney cells...
  11. Haase V. The VHL tumor suppressor in development and disease: functional studies in mice by conditional gene targeting. Semin Cell Dev Biol. 2005;16:564-74 pubmed
    The von Hippel-Lindau tumor suppressor pVHL plays a critical role in the pathogenesis of familial and sporadic clear cell carcinomas of the kidney and hemangioblastomas of the retina and central nervous system...
  12. Puri S, Cano D, Hebrok M. A role for von Hippel-Lindau protein in pancreatic beta-cell function. Diabetes. 2009;58:433-41 pubmed publisher
    The Vhlh gene codes for the von Hippel-Lindau protein (VHL), a tumor suppressor that is a key player in the cellular response to oxygen sensing...
  13. Chan S, Zhang Y, Hemann C, Mahoney C, Zweier J, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009;10:273-84 pubmed publisher
    ..These results identify important mechanistic connections among microRNA, iron-sulfur cluster biology, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to cellular stress. ..
  14. Ohh M, Yauch R, Lonergan K, Whaley J, Stemmer Rachamimov A, Louis D, et al. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell. 1998;1:959-68 pubmed
    Fibronectin coimmunoprecipitated with wild-type von Hippel-Lindau protein (pVHL) but not tumor-derived pVHL mutants...
  15. Rankin E, Biju M, Liu Q, Unger T, Rha J, Johnson R, et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest. 2007;117:1068-77 pubmed
    ..We have previously shown that inactivation of the von Hippel-Lindau tumor suppressor pVHL, which targets both HIFs for proteasomal degradation, results in increased hepatic Epo production and polycythemia ..
  16. Cantley J, Selman C, Shukla D, Abramov A, Forstreuter F, Esteban M, et al. Deletion of the von Hippel-Lindau gene in pancreatic beta cells impairs glucose homeostasis in mice. J Clin Invest. 2009;119:125-35 pubmed publisher
    ..The von Hippel-Lindau (VHL) protein controls the degradation of hypoxia-inducible factor (HIF) to coordinate cellular and organismal responses ..
  17. Weidemann A, Kerdiles Y, Knaup K, Rafie C, Boutin A, Stockmann C, et al. The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest. 2009;119:3373-83 pubmed publisher
    ..hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha and their negative regulator von Hippel-Lindau (VHL) as well as astrocyte-specific deletion of the HIF target gene Vegf...
  18. Lei L, Mason S, Liu D, Huang Y, Marks C, Hickey R, et al. Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. Mol Cell Biol. 2008;28:3790-803 pubmed publisher
    ..We generated mice with cardiac myocyte-specific deletion of the von Hippel-Lindau protein (VHL), an essential component of an E3 ubiquitin ligase responsible for suppressing HIF levels during normoxia...
  19. Choi D, Cai E, Schroer S, Wang L, Woo M. Vhl is required for normal pancreatic ? cell function and the maintenance of ? cell mass with age in mice. Lab Invest. 2011;91:527-38 pubmed publisher
    ..are involved in angiogenesis, survival, proliferation, and energy metabolism, and von Hippel-Lindau protein (VHL) is a negative regulator of this pathway...
  20. Hickey M, Lam J, Bezman N, Rathmell W, Simon M. von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest. 2007;117:3879-89 pubmed
    The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated ..
  21. Park S, Haase V, Johnson R. von Hippel Lindau tumor suppressor regulates hepatic glucose metabolism by controlling expression of glucose transporter 2 and glucose 6-phosphatase. Int J Oncol. 2007;30:341-8 pubmed
    von Hippel Lindau (VHL) disease is a hereditary cancer syndrome caused by biallelic inactivation of the VHL tumor suppressor gene...
  22. Kleymenova E, Everitt J, Pluta L, Portis M, Gnarra J, Walker C. Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice. Carcinogenesis. 2004;25:309-15 pubmed
    The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of renal cell carcinoma (RCC) in humans...
  23. Lolkema M, Mans D, Snijckers C, van Noort M, van Beest M, Voest E, et al. The von Hippel-Lindau tumour suppressor interacts with microtubules through kinesin-2. FEBS Lett. 2007;581:4571-6 pubmed
    ..Recent studies indicate that this regulation is linked to microtubule-dependent functions of pVHL such as orienting microtubule growth and increasing plus-end microtubule stability, however little is known how ..
  24. Pfander D, Kobayashi T, Knight M, Zelzer E, Chan D, Olsen B, et al. Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development. Development. 2004;131:2497-508 pubmed
    ..We have used conditional inactivation of murine VHL (Vhlh) in all cartilaginous elements to investigate its role in endochondral bone development...
  25. Kessler P, Vasavada S, Rackley R, Stackhouse T, Duh F, Latif F, et al. Expression of the Von Hippel-Lindau tumor suppressor gene, VHL, in human fetal kidney and during mouse embryogenesis. Mol Med. 1995;1:457-66 pubmed
    Von Hippel-Lindau (VHL) disease is a familial cancer syndrome that has a dominant inherited pattern which predisposes affected individuals to a variety of tumours...
  26. Kurihara T, Kubota Y, Ozawa Y, Takubo K, Noda K, Simon M, et al. von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina. Development. 2010;137:1563-71 pubmed publisher
    ..The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate recognition component of an E3-ubiquitin ligase that rapidly destabilizes hypoxia-inducible factor ..
  27. Gnarra J, Ward J, Porter F, Wagner J, Devor D, Grinberg A, et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci U S A. 1997;94:9102-7 pubmed
    Inheritance of an inactivated form of the VHL tumor suppressor gene predisposes patients to develop von Hippel-Lindau disease, and somatic VHL inactivation is an early genetic event leading to the development of sporadic renal cell ..
  28. Voss A, Thomas T, Gruss P. Mice lacking HSP90beta fail to develop a placental labyrinth. Development. 2000;127:1-11 pubmed
    ..The allantois mesoderm is thought to induce trophoblast differentiation. Our results show that Hsp90beta is a necessary component of this induction process. ..
  29. Thoma C, Toso A, Gutbrodt K, Reggi S, Frew I, Schraml P, et al. VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol. 2009;11:994-1001 pubmed publisher
    ..Here we show that the von Hippel-Lindau (VHL) tumour suppressor protein, pVHL, which is inactivated in hereditary and sporadic forms of renal cell carcinoma, localizes to the mitotic spindle in ..
  30. Shen H, Adem A, Ylaya K, Wilson A, He M, Lorang D, et al. Deciphering von Hippel-Lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations. PLoS ONE. 2009;4:e4897 pubmed publisher
    ..In addition, deficiency of VHL protein (pVHL) in terminally differentiated alpha-cells or beta-cells is insufficient to induce pancreatic neuroendocrine ..
  31. Parikh V, Jin R, Rabello S, Gulbahce N, White K, Hale A, et al. MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation. 2012;125:1520-32 pubmed publisher
    ..Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying microRNA in PH. ..
  32. Zehetner J, Danzer C, Collins S, Eckhardt K, Gerber P, Ballschmieter P, et al. PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells. Genes Dev. 2008;22:3135-46 pubmed publisher
    ..Conditional inactivation of Vhlh in beta cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to ..
  33. Iguchi M, Kakinuma Y, Kurabayashi A, Sato T, Shuin T, Hong S, et al. Acute inactivation of the VHL gene contributes to protective effects of ischemic preconditioning in the mouse kidney. Nephron Exp Nephrol. 2008;110:e82-90 pubmed publisher
    The von Hippel-Lindau (VHL) protein functions as an E3 ubiquitin ligase, controlling the stability of hypoxia-inducible factor (HIF)...
  34. Biju M, Neumann A, Bensinger S, Johnson R, Turka L, Haase V. Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol. 2004;24:9038-47 pubmed
    The von Hippel-Lindau gene product (pVHL) targets the alpha subunit of basic helix-loop-helix transcription factor hypoxia-inducible factor (HIF) for proteasomal degradation...
  35. Champion K, Guinea M, Dammai V, Hsu T. Endothelial function of von Hippel-Lindau tumor suppressor gene: control of fibroblast growth factor receptor signaling. Cancer Res. 2008;68:4649-57 pubmed publisher
    von Hippel-Lindau (VHL) disease results from germline and somatic mutations in the VHL tumor suppressor gene and is characterized by highly vascularized tumors...
  36. Rankin E, Tomaszewski J, Haase V. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res. 2006;66:2576-83 pubmed
    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...
  37. Kapitsinou P, Haase V. The VHL tumor suppressor and HIF: insights from genetic studies in mice. Cell Death Differ. 2008;15:650-9 pubmed publisher
    The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive alpha-subunit of hypoxia-inducible factor (HIF) for rapid ..
  38. Wang Y, Wan C, Deng L, Liu X, Cao X, Gilbert S, et al. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest. 2007;117:1616-26 pubmed
    ..Mice overexpressing HIF alpha in osteoblasts through selective deletion of the von Hippel-Lindau gene (Vhl) expressed high levels of Vegf and developed extremely dense, heavily vascularized long bones...
  39. Lee S, Che X, Jeong J, Choi J, Lee Y, Lee Y, et al. Runx2 protein stabilizes hypoxia-inducible factor-1? through competition with von Hippel-Lindau protein (pVHL) and stimulates angiogenesis in growth plate hypertrophic chondrocytes. J Biol Chem. 2012;287:14760-71 pubmed publisher
    ..In conclusion, Runx2, HIF-1?, and VEGF may regulate vascular angiogenesis spatially and temporally in the hypertrophic zone of the growth plate during endochondral bone formation. ..
  40. Rastaldi M. Necrotizing crescentic glomerulonephritis--a conditional knockout model discloses new therapeutic challenges. Nephrol Dial Transplant. 2007;22:1020-2 pubmed
  41. Ramakrishnan S, Taylor M, Qu A, Ahn S, Suresh M, Raghavendran K, et al. Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2? and regulation of bile acid homeostasis. Mol Cell Biol. 2014;34:1208-20 pubmed publisher
    ..The present study demonstrates that hypoxic activation of hepatic HIF-2? leads to an adaptive increase in cholesterol levels through inhibition of bile acid synthesis. ..
  42. Urrutia A, Afzal A, Nelson J, Davidoff O, Gross K, Haase V. Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes. Blood. 2016;128:2550-2560 pubmed
    ..Our findings furthermore suggest that the ability to synthesize EPO may represent a functional feature of pericytes in the brain and kidney. ..
  43. Devignes C, Aslan Y, Brenot A, Devillers A, Schepers K, Fabre S, et al. HIF signaling in osteoblast-lineage cells promotes systemic breast cancer growth and metastasis in mice. Proc Natl Acad Sci U S A. 2018;115:E992-E1001 pubmed publisher
    ..They also support the concept that the skeleton is an important regulator of the systemic tumor environment. ..
  44. Hickey M, Richardson T, Wang T, Mosqueira M, Arguiri E, Yu H, et al. The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest. 2010;120:827-39 pubmed publisher
    Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia...
  45. Mack F, Patel J, Biju M, Haase V, Simon M. Decreased growth of Vhl-/- fibrosarcomas is associated with elevated levels of cyclin kinase inhibitors p21 and p27. Mol Cell Biol. 2005;25:4565-78 pubmed
    ..b>pVHL targets alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF), a critical ..
  46. Steenhard B, Isom K, Stroganova L, St John P, Zelenchuk A, Freeburg P, et al. Deletion of von Hippel-Lindau in glomerular podocytes results in glomerular basement membrane thickening, ectopic subepithelial deposition of collagen {alpha}1{alpha}2{alpha}1(IV), expression of neuroglobin, and proteinuria. Am J Pathol. 2010;177:84-96 pubmed publisher
    ..A component of the E3 ubiquitin ligase complex, von Hippel-Lindau (VHL) facilitates oxygen-dependent polyubiquitination and proteasomal degradation of HIFalpha subunits...
  47. Woodward E, Buchberger A, Clifford S, Hurst L, Affara N, Maher E. Comparative sequence analysis of the VHL tumor suppressor gene. Genomics. 2000;65:253-65 pubmed
    ..Although most of the regions in pVHL that had been implicated in binding specific proteins demonstrated evolutionary conservation, the carboxy-terminal ..
  48. Schönenberger D, Harlander S, Rajski M, Jacobs R, Lundby A, Adlesic M, et al. Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α. Cancer Res. 2016;76:2025-36 pubmed publisher
    ..One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the ..
  49. Cowburn A, Takeda N, Boutin A, Kim J, Sterling J, Nakasaki M, et al. HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci U S A. 2013;110:17570-5 pubmed publisher
    ..Thus, the balance between HIF-1α and HIF-2α expression in keratinocytes is a control element of both tissue perfusion and systemic arterial pressure, with potential implications in human hypertension. ..
  50. Neumann A, Yang J, Biju M, Joseph S, Johnson R, Haase V, et al. Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci U S A. 2005;102:17071-6 pubmed
    ..Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1alpha under "normoxic" conditions, we ..
  51. White K, Lu Y, Annis S, Hale A, Chau B, Dahlman J, et al. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol Med. 2015;7:695-713 pubmed publisher
    ..These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings. ..
  52. Puri S, Akiyama H, Hebrok M. VHL-mediated disruption of Sox9 activity compromises ?-cell identity and results in diabetes mellitus. Genes Dev. 2013;27:2563-75 pubmed publisher
    ..Using transgenic mouse models, we demonstrate that deletion of the von Hippel-Lindau (Vhlh) gene (encoding an E3 ubiquitin ligase implicated in, among other functions, oxygen sensing in pancreatic ? cells) ..
  53. Farsijani N, Liu Q, Kobayashi H, Davidoff O, Sha F, Fandrey J, et al. Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. J Clin Invest. 2016;126:1425-37 pubmed publisher
    ..Our genetic analysis suggests that tubulointerstitial cellular crosstalk modulates renal EPO production under conditions of epithelial HIF activation in the kidney. ..
  54. Le Moan N, Baeten K, Rafalski V, Ryu J, Rios Coronado P, Bédard C, et al. Hypoxia Inducible Factor-1α in Astrocytes and/or Myeloid Cells Is Not Required for the Development of Autoimmune Demyelinating Disease,. Eneuro. 2015;2: pubmed
  55. Zhang L, Qi J, Zuo G, Jia P, Shen X, Shao J, et al. Osteoblast-secreted factors promote proliferation and osteogenic differentiation of bone marrow stromal cells via VEGF/heme-oxygenase-1 pathway. PLoS ONE. 2014;9:e99946 pubmed publisher
    ..Mice lacking von Hippel-Lindau gene (Vhl), thus overexpressing HIF? in osteoblasts develop extremely dense and highly vascularized long bones...
  56. Puri S, García Núñez A, Hebrok M, Cano D. Elimination of von Hippel-Lindau function perturbs pancreas endocrine homeostasis in mice. PLoS ONE. 2013;8:e72213 pubmed publisher
    Mutations in the human homolog of the Vhlh gene [encoding the von-Hippel Lindau (VHL) protein] lead to tumor development...
  57. Takubo K, Nagamatsu G, Kobayashi C, Nakamura Ishizu A, Kobayashi H, Ikeda E, et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell. 2013;12:49-61 pubmed publisher
    ..Moreover, treatment of HSCs with a Pdk mimetic promoted their survival and transplantation capacity. Thus, glycolytic metabolic status governed by Pdk acts as a cell cycle checkpoint that modulates HSC quiescence and function. ..
  58. Miró Murillo M, Elorza A, Soro Arnaiz I, Albacete Albacete L, Ordoñez A, Balsa E, et al. Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression. PLoS ONE. 2011;6:e22589 pubmed publisher
    Von Hippel Lindau (Vhl) gene inactivation results in embryonic lethality...
  59. Park S, Dadak A, Haase V, Fontana L, Giaccia A, Johnson R. Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1alpha (HIF-1alpha): role of cytoplasmic trapping of HIF-2alpha. Mol Cell Biol. 2003;23:4959-71 pubmed
  60. Pritchett T, Bader H, Henderson J, Hsu T. Conditional inactivation of the mouse von Hippel-Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney. Oncogene. 2015;34:2631-9 pubmed publisher
    ..To understand the progression of ccRCC, we generated a novel mouse Vhlh conditional knockout, using Hoxb7-driven Cre that is specific for the collecting ducts and a subset of distal ..
  61. Hardy M, O Neill L. The murine IRAK2 gene encodes four alternatively spliced isoforms, two of which are inhibitory. J Biol Chem. 2004;279:27699-708 pubmed
    ..These observations identify another distinguishing feature between mice and humans in the TLR system that is likely to be due to differences in the selective pressure imposed by pathogens on each species during evolution. ..
  62. Zhang C, Liu Q, Li M, Lin S, Peng Y, Wu D, et al. RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect. Cell Res. 2015;25:1025-42 pubmed publisher
    ..RHOBTB3 also directly interacts with the von Hippel-Lindau (VHL) protein, a component of the E3 ubiquitin ligase complex, facilitating ubiquitination of HIFα...
  63. Yokoe S, Nakagawa T, Kojima Y, Higuchi K, Asahi M. Indomethacin-induced intestinal epithelial cell damage is mediated by pVHL activation through the degradation of collagen I and HIF-1α. Biochem Biophys Res Commun. 2015;468:671-6 pubmed publisher
    ..play an important role, herein, we focused on one of the major ubiquitin E3 ligases, the von Hippel-Lindau protein (pVHL)...
  64. Minamishima Y, Moslehi J, Bardeesy N, Cullen D, Bronson R, Kaelin W. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008;111:3236-44 pubmed
    ..The latter is likely the result of hyperviscosity syndrome and volume overload, although a direct effect of chronic, high-level HIF stimulation on cardiac myocytes cannot be excluded. ..
  65. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7:391-402 pubmed publisher
    ..Overstabilization of HIF-1alpha by biallelic loss of an E3 ubiquitin ligase for HIF-1alpha (VHL) induced cell cycle quiescence in HSCs and their progenitors but resulted in an impairment in transplantation ..
  66. Harlander S, Schönenberger D, Toussaint N, Prummer M, Catalano A, Brandt L, et al. Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice. Nat Med. 2017;23:869-877 pubmed publisher
    ..cell renal cell carcinomas (ccRCCs) frequently exhibit inactivation of the von Hippel-Lindau tumor-suppressor gene, VHL, and often harbor multiple copy-number alterations in genes that regulate cell cycle progression...
  67. Gnarra J, Duan D, Weng Y, Humphrey J, Chen D, Lee S, et al. Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma. Biochim Biophys Acta. 1996;1242:201-10 pubmed