| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| The von Hippel Lindau tumor suppressor protein ( pVHL ) regulates the stability of HIF 1 alpha and HIF 2 alpha and thus is pivotal in cellular responses to changes in oxygen tension . ^^^ In situ , pVHL immunolocalized to villous cytotrophoblast stem cells , and expression was enhanced at sites of cell column initiation ; in both of these relatively hypoxic locations , cytoplasmic staining for HIF 2 alpha was also detected . ^^^ As cytotrophoblasts attached to and invaded the uterus , which results in their increased exposure to oxygen , pVHL staining was abruptly downregulated concordant with localization of HIF 2 alpha to the nucleus . ^^^ In vitro , hypoxia ( 2 % O ( 2 ) ) upregulated cytotrophoblast pVHL expression together with HIF 2 alpha , which localized to the cytoplasm ; culture under well oxygenated conditions greatly reduced levels of both molecules . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| VHL functions in the destruction of the alpha subunits of the heterodimeric transcription factor , hypoxia inducible factor ( HIF 1 alpha and HIF 2 alpha ) , in normoxic conditions . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| We report here that small inhibitory RNA ( siRNA ) knockdown of Nox 4 in 786 0 human renal tumor cells expressing empty vector ( PRC ) or wild type VHL ( WT ) results in 50 % decrease in intracellular reactive oxygen species as measured by a fluorescent 2 ' , 7 ' dichlorofluorescin diacetate assay , and > 85 % reduction in HIF 2 alpha mRNA and protein levels by quantitative reverse transcription PCR and Western blot analysis . ^^^ Thus , renal Nox 4 expression is essential for full HIF 2 alpha expression and activity in 786 0 renal tumor cells , even in the absence of functional VHL . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| In a previous study of hemangioblastomas , the most frequent manifestation of hereditary von Hippel Lindau disease ( VHL ) , we found elevated levels of vascular endothelial growth factor and HIF 2alpha mRNA in stromal cells of the tumors . ^^^ In this study , we analysed the expression of the hypoxia inducible factors HIF 1alpha and HIF 2alpha in a range of VHL wildtype and VHL deficient RCC cell lines . ^^^ In the presence of functional VHL protein , HIF 1alpha mRNA levels are elevated , whereas HIF 2alpha mRNA expression is increased only in cells lacking a functional VHL gene product . ^^^ On the protein levels , however , in VHL deficient cell lines , both HIF alpha subunits are constitutively expressed , whereas re introduction of a functional VHL gene restores the instability of HIF 1alpha and HIF 2alpha proteins under normoxic conditions . ^^^ The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF 1alpha and HIF 2alpha proteins . . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Effects of ras and von Hippel Lindau ( VHL ) gene mutations on hypoxia inducible factor ( HIF ) 1alpha , HIF 2alpha , and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3 ' kinase / Akt signaling pathway . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| In normal cells the product of the VHL tumour suppressor gene targets the regulatory HIF subunits ( HIF 1alpha and HIF 2alpha ) for oxygen dependent proteolysis , acting as the substrate recognition component of an E 3 ubiquitin ligase . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Importantly , HIF 1alpha Pro 564 and HIF 2alpha Pro 531 hydroxylation is diminished with the treatment of hypoxia , cobalt chloride , desferrioxamine , or dimethyloxalyglycine , regardless of the E 3 ubiquitin ligase activity of the von Hippel Lindau ( VHL ) tumor suppressor gene . ^^^ Furthermore , in VHL deficient cells , HIF 1alpha Pro 564 and HIF 2alpha Pro 531 had detectable amounts of hydroxylation following transition to hypoxia , indicating that the post translational modification is not reversible . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| The von Hippel Lindau protein ( pVHL ) mediates the ubiquitination and rapid degradation of HIF alpha ( including HIF 1alpha and HIF 2alpha ) . ^^^ Deletion of 17 amino acids within the ODD domain of HIF 2alpha that are required for pVHL binding prevented the binding of cobalt and stabilized HIF 2alpha during normoxia . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Chorionic gonadotropin regulates the transcript level of VHL , p 53 , and HIF 2alpha in human granulosa lutein cells . ^^^ In addition , we showed that hCG regulates the expression of p 53 , VHL , and HIF 2alpha . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Finally , RNAi mediated knockdown of the Cul 2 Rbx1 inhibited the VHL mediated degradation of HIF 2alpha , whereas knockdown of Cul 5 Rbx2 did not affect it . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Furthermore , we demonstrate that in addition to S65L , five other tumor derived VHL mutations located within the L 1 loop are each defective in mediating proteolysis of HIF 2alpha . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Over expression of the hypoxia inducible transcription factor , HIF 2alpha , in norepinephrine predominant sporadic and VHL tumors compared with epinephrine producing tumors indicates that expression of this gene depends on the noradrenergic biochemical phenotype . ^^^ The findings fit with the known expression of HIF 2alpha in norepinephrine producing cells of the sympathetic nervous system and might explain both the development and noradrenergic biochemical phenotype of pheochromocytomas in VHL syndrome . . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| The 2alpha form of HIF ( HIF 2alpha ) , but not HIF 1alpha , drives in vitro and in vivo tumorigenesis of VHL / RCC cells by specifically activating the TGF alpha / EGFR pathway . ^^^ These data identify EGFR as a critical determinant of HIF 2alpha dependent tumorigenesis and show at the molecular level that EGFR remains a credible target for therapeutic strategies against VHL / renal carcinoma . . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Defective function of the von Hippel Lindau ( VHL ) tumor suppressor ablates proteolytic regulation of hypoxia inducible factor alpha subunits ( HIF 1alpha and HIF 2alpha ) , leading to constitutive activation of hypoxia pathways in renal cell carcinoma ( RCC ) . ^^^ In VHL defective RCC cells , we demonstrate that the protumorigenic genes encoding cyclin D 1 , transforming growth factor alpha , and vascular endothelial growth factor respond specifically to HIF 2alpha and that the proapoptotic gene encoding BNip 3 responds positively to HIF 1alpha and negatively to HIF 2alpha , indicating that HIF 1alpha and HIF 2alpha have contrasting properties in the biology of RCC . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Additionally , 786 O cells reconstituted with wild type VHL and with a constitutively active form of HIF 2alpha did not reproduce any of the phenotypic alterations of VHL negative cells . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| Consistent , simultaneous over expression of HIF 1alpha and HIF 2alpha appears to be specific to VHL negative clear cell renal cell carcinoma . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| HIF 2alpha repression may explain why patients with mutations in the VHL tumor suppressor gene display cancerous lesions in specific tissue types . . ^^^ |
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| Interacting proteins: Q99814 and P40337 |
Pubmed |
SVM Score :0.0 |
| To address this , we used small interfering RNA ( siRNA ) techniques to knockdown HIF 1alpha and / or HIF 2alpha expression in response to hypoxia , insulin like growth factor ( IGF ) 1 , or renal carcinoma cells expressing constitutively high basal levels of HIF 1alpha and / or HIF 2alpha due to loss of von Hippel Lindau ( VHL ) function . ^^^ In contrast , in renal carcinoma cells that constitutively express HIF 1alpha and HIF 2alpha due to loss of VHL function , we found that high basal VEGF , glucose transporter 1 , urokinase type plasminogen activator receptor , and plasminogen activator inhibitor 1 expression was predominantly dependent on HIF 2alpha . ^^^ |
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