| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.68490894 |
| Hydroxylation of at least two prolyl residues in the oxygen dependent degradation domain of HIF 1 alpha regulates its interaction with the von Hippel Lindau protein ( VHL ) that targets HIF 1 alpha for ubiquitination and proteasomal degradation . 0.68490894^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.81947375 |
| The 1 . 85 angstrom structure of a 20 residue HIF 1alpha peptide pVHL ElonginB ElonginC complex shows that HIF 1alpha binds to pVHL in an extended beta strand like conformation . 0.81947375^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| During the course of nephrotoxicity , levels of pVHL , a factor that destabilizes HIF 1 alpha , increased significantly . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Antisense thioredoxin inhibits angiogenesis via pVHL mediated hypoxia inducible factor 1alpha degradation . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| VHL is required for oxygen dependent degradation of hypoxia inducible factor 1alpha ( HIF 1alpha ) . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Histone deacetylase inhibitors induce VHL and ubiquitin independent proteasomal degradation of hypoxia inducible factor 1alpha . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The stability and activity of HIF 1alpha are regulated by binding to various proteins such as pVHL , p 53 , and p300 / CBP . ^^^ |
|
| Interacting proteins: Q16665 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 ) . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Gene silencing of HIF 1alpha by small interfering RNA reduced p 21 and p 27 protein and mRNA levels in Vhl ( ) ( / ) ( ) MEFs . ^^^ |
|
| Interacting proteins: Q16665 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 . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| ARD 1 , the acetyltransferase , acetylates HIF 1a at lysine 532 , which enhances the interaction of HIF 1a with pVHL . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Here we show that the product of the von Hippel Lindau ( VHL ) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of HIF 1 alpha under normoxic conditions via interaction with the core of the oxygen dependent degradation domain of HIF 1 alpha . ^^^ The region of VHL mediating interaction with HIF 1 alpha overlapped with a putative macromolecular binding site observed within the crystal structure of VHL . ^^^ This motif of VHL also represents a mutational hotspot in tumors , and one of these mutations impaired interaction with HIF 1 alpha and subsequent degradation . ^^^ Interestingly , the VHL binding site within HIF 1 alpha overlapped with one of the minimal transactivation domains . ^^^ Protection of HIF 1 alpha against degradation by VHL was a multistep mechanism , including hypoxia induced nuclear translocation of HIF 1 alpha and an intranuclear hypoxia dependent signal . ^^^ |
|
| Interacting proteins: Q16665 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 . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau ( VHL ) dependent destabilization and tagging of HIF 1 alpha . ^^^ The absolute dependence of the PFKFB 3 gene on HIF 1 was confirmed by its overexpression in VHL deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF 1 alpha . . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| HIF 1 alpha is stable in hypoxia , but in the presence of oxygen it is targeted for proteasomal degradation by the ubiquitination complex pVHL , the protein of the von Hippel Lindau ( VHL ) tumour suppressor gene and a component of an E 3 ubiquitin ligase complex . ^^^ Structural basis for the recognition of hydroxyproline in HIF 1 alpha by pVHL . ^^^ Capture of HIF 1 alpha by pVHL is regulated by hydroxylation of specific prolyl residues in two functionally independent regions of HIF 1 alpha . ^^^ The crystal structure of a hydroxylated HIF 1 alpha peptide bound to VCB ( pVHL , elongins C and B ) and solution binding assays reveal a single , conserved hydroxyproline binding pocket in pVHL . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Although the von Hippel Lindau ( VHL ) gene product , the ubiquitin ligase responsible for regulating HIF 1 alpha protein levels , efficiently targets HIF 1 alpha for rapid proteasome dependent degradation under normoxia , HIF 1 alpha is resistant to the destabilizing effects of VHL under hypoxia . ^^^ To examine the role of Hsp 90 in HIF 1 alpha function , we used renal carcinoma cell ( RCC ) lines that lack functional VHL and express stable HIF 1 alpha protein under normoxia . ^^^ Furthermore , HIF 1 alpha point mutations that block VHL association did not protect HIF 1 alpha from GA induced destabilization . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Finally , TNF failed to induce both HIF 1 alpha , made resistant to von Hippel Lindau ( VHL ) , and wild type HIF 1 alpha transfected into VHL ( / ) cells . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| By using computer modeling , we identified regions of Rpb 1 and the adjacent subunit 6 of RNA polymerase 2 ( Rpb 6 ) that share sequence and structural similarity with the domain of hypoxia inducible transcription factor 1 alpha ( HIF 1 alpha ) that binds von Hippel Lindau tumor suppressor protein ( pVHL ) . pVHL confers substrate specificity to the E 3 ligase complex , which ubiquitinates HIF alpha and targets it for proteasomal degradation . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Previous results have revealed a role for prolyl hydroxylation and resultant von Hippel Lindau protein ( pVHL ) interactions in the ubiquitin proteasome mediated degradation of HIF 1 alpha . ^^^ However , neither inhibition of prolyl hydroxylases nor mutation of HIF 1 alpha hydroxylated prolines involved with pVHL mediated binding inhibits the observed FOXO 4 mediated down regulation of HIF 1 alpha . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| In hypoxia or secondary to a mutated VHL gene , the nondegraded HIF 1 alpha forms a heterodimer with HIF beta and leads to increased transcription of hypoxia inducible genes , including erythropoietin ( EPO ) . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The VHL protein targets hypoxia inducible factor 1 alpha ( HIF 1 alpha ) , a transcription factor that can induce vascular endothelial growth factor ( VEGF ) expression , for ubiquitination and degradation . ^^^ Accumulation of HIF 1 alpha caused by mutant VHL protein in tumor cells may result in VEGF over expression , which has been used to explain the increased vascularity of RCC . ^^^ However , quantitative analyses of VEGF production and its correlation with VHL mutations and HIF 1 alpha expression in authentic tissues from patients with RCC are lacking . ^^^ HIF 1 alpha protein expression was found in 40 % of clear cell RCCs but 80 % of them had VHL mutations ( p < 0 . 006 ) . ^^^ CONCLUSIONS : Our findings indicate that VHL gene alterations and HIF 1 alpha protein expression correlate with a significant increase in VEGF production by RCC . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The protein pVHL functions in a multi subunit E 3 ubiquitin ligase that targets the hypoxia inducible transcription factor Hif 1 alpha for proteasomal degradation during normoxia . ^^^ TBP 1 associates with the beta domain of pVHL and complexes with pVHL and Hif 1 alpha in vivo . ^^^ Overexpression of TBP 1 promotes degradation of Hif 1 alpha in a pVHL dependent manner that requires the ATPase domain of TBP 1 . ^^^ A pVHL mutant containing a P154L substitution coimmunoprecipitates with Hif 1 alpha , but not TBP 1 , and does not promote degradation of Hif 1 alpha . ^^^ Thus , the ability of pVHL to degrade Hif 1 alpha depends in part on its interaction with TBP 1 and suggests a new mechanism for Hif 1 alpha stabilization in some pVHL deficient tumors . . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| To aid in an analysis of the VHL protein regulation of HIF 1 alpha degradation , an important and only partially understood process that directly influences angiogenesis , we performed a comprehensive search for the orthologs of the VHL as well as for VHL interacting proteins in all the available eukaryotic genomes . ^^^ We have also shown that relation trees derived from the multiple sequence alignment , functional surface mapping , and HIF 1 alpha degradation pathway structure are in complete agreement , linking the functional and structural evolution of the VHL protein and VHL dependent HIF 1 alpha degradation complex . . ^^^ |
|
| Interacting proteins: Q16665 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 . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| After treatment , the following processes and factors were monitored : apoptosis , cellular metabolism and viability , expression of genes encoding HIF1A , von Hippel Lindau tumor suppressor protein ( VHL ) , and genes responsible for cell death induction and antiapoptotic defense ( P 53 , BCL 2 , BAX , and caspases 9 and 3 ) . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| One such specific subdomain , the DUSP domain ( domain present in ubiquitin specific proteases ) , is present in at least seven different human USPs that regulate the stability of or interact with the hypoxia inducible transcription factor HIF 1 alpha , the Von Hippel Lindau protein ( pVHL ) , cullin E 3 ligases , and BRCA 2 . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Growth arrest caused by CCI 779 correlates with a block in translation of mRNA encoding hypoxia inducible factor ( HIF1A ) , and is rescued by expression of a VHL resistant HIF1A cDNA lacking the 5 ' untranslated region . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| HIF is stable and initiates gene transcription under hypoxia , whereas in normoxia , interaction with the von Hippel Lindau tumor suppressor protein ( VHL ) leads to rapid degradation of the HIF1A subunit . ^^^ Expression of HIF1A and VHL was high at 7 9 wk of gestation , when oxygen tension is low , and decreased when placental oxygen tension increases ( 10 12 wk of gestation ) . ^^^ During early placentation , HIF1A localized in cytotrophoblasts , while VHL was present in syncytiotrophoblasts . ^^^ At 10 12 wk , VHL appeared in cytotrophoblast cells , which coincided with the disappearance of HIF1A . ^^^ At the same time the association of VHL and Cullin 2 as well as ubiquitination of HIF1A was maximal . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| At normoxia , HIF 1 alpha is targeted by the von Hippel Lindau tumor suppressor protein ( pVHL ) for degradation by the ubiquitin proteasome pathway . ^^^ In the present study we have observed distinct cell type specific differences in the ability of various tested pVHL interacting subfragments to stabilize HIF 1 alpha and unmask its function at normoxia . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Here we demonstrate that both nonselective ( indomethacin ) and COX 2 selective ( NS 398 ) NSAIDs inhibit hypoxia induced in vitro angiogenesis in gastric microvascular endothelial cells via coordinated sequential events : 1 ) increased expression of the von Hippel Lindau ( VHL ) tumor suppressor , which targets proteins for ubiquitination leading to 2 ) reduced accumulation of hypoxia inducible factor 1alpha ( HIF 1alpha ) and , as a result , 3 ) reduced expression of vascular endothelial growth factor ( VEGF ) and its specific receptor Flt 1 . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The tumor suppressor von Hippel Lindau ( VHL ) participates in the hypoxia sensing pathway , as it binds to the proline hydroxylated form of the hypoxia inducible factor 1alpha ( HIF 1alpha ) and mediates its ubiquitination and proteosomal degradation . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Under normoxic conditions the hypoxia inducible factor 1alpha ( HIF 1alpha ) protein is targeted for degradation by the von Hippel Lindau ( pVHL ) tumor suppressor protein acting as an E 3 ubiquitin ligase . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Expression of genes responsive to cellular oxygen concentration , hypoxia inducible factor 1alpha ( HIF 1alpha ) , three splicing variants of vascular endothelial growth factor ( VEGF ) and von Hippel Lindau protein ( pVHL ) was measured by reverse transcription polymerase chain reaction ( RT PCR ) in 12 Cerro de Pasco ( CP ) ( altitude 4338 m ) natives and 15 CMS patients in CP . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The von Hippel Lindau tumor suppressor ( pVHL ) is a component of an E 3 ubiquitin ligase and targets hypoxia inducible factor 1alpha ( HIF 1alpha ) for ubiquitylation and degradation under normoxic conditions . pVHL also directly inhibits HIF 1alpha transactivation by recruiting histone deacetylases . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The VHL gene normally regulates ubiquitin mediated proteolysis of hypoxia inducible factor 1alpha ( HIF 1alpha ) ; in cell lines , VHL inactivation blocks HIF 1alpha proteolysis , resulting in increased HIF 1 expression . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| A key task for the multifunctional von Hippel Lindau protein ( pVHL ) is regulation of the activity of hypoxia inducible factor 1alpha ( HIF 1alpha ) by targeting it to the proteasome for degradation under normoxia . pVHL binding to HIF 1alpha is lost under low O 2 tension , leading to transcription of several genes involved in the hypoxia response . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The hypervascular nature of VHL lesions has been linked to the overproduciton of vascular endothelial growth factor ( VEGF ) through increased expression of hypoxia inducible factor 1alpha ( HIF 1alpha ) . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| In RCC 4 and RCC 786 0 VHL cells with VHL mutations , the protein of hypoxia inducible factor 1alpha ( HIF 1alpha ) is constitutively stabilized and the mRNA levels of HIF target genes , including vascular endothelial growth factor ( VEGF ) , are elevated . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| BACKGROUND : Hypoxia inducible factor 1alpha ( HIF 1alpha ) regulates cellular responses to hypoxia and is rapidly degraded under normoxia through von Hippel Lindau ( VHL ) mediated ubiquitination . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The majority of these tumors lack functional VHL protein ( pVHL ) that leads to increased hypoxia inducible factor 1alpha ( HIF 1alpha ) expression . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Hypoxia inducible factor 1alpha ( HIF 1alpha ) induction and associated transcription were investigated during high cell density , focusing on the negative regulator of HIF 1alpha expression , the von Hippel Lindau ( VHL ) protein . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| 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 . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Von Hippel Lindau protein ( pVHL ) normally functions to cause ubiquitin mediated degradation of hypoxia inducible factor 1alpha ( HIF 1alpha ) under normoxic but not under hypoxic conditions , and induces neuronal differentiation of neural progenitor cells . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The mechanism by which hypoxia induces gene transcription involves the inhibition of HIF 1alpha ( hypoxia inducible factor 1 alpha subunit ) PHD ( prolyl hydroxylase ) activity , which prevents the VHL ( von Hippel Lindau ) dependent targeting of HIF 1alpha to the ubiquitin / proteasome pathway . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Chuvash polycythemia is characterized by a homozygous 598C > T germline mutation in the von Hippel Lindau gene ( VHL ) , upregulation of hypoxia inducible factor 1alpha during normoxia , and resulting augmentation of erythropoietin and several other hypoxia controlled genes . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The von Hippel Lindau tumor suppressor , pVHL , forms part of an E 3 ubiquitin ligase complex that targets specific substrates for degradation , including hypoxia inducible factor 1alpha ( HIF 1alpha ) , which is involved in tumor progression and angiogenesis . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| 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 . . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| HIF 1alpha binding to VHL is regulated by stimulus sensitive proline hydroxylation . ^^^ Under normoxic conditions , HIF 1alpha is recognized by the von Hippel Lindau tumor suppressor protein ( VHL ) , a component of an E 3 ubiquitin ligase complex . ^^^ We have previously shown that VHL binds in a hypoxia sensitive manner to a 27 aa segment of HIF 1alpha , and that this regulation depends on a posttranslational modification of HIF 1alpha . ^^^ Through a combination of in vivo coimmunoprecipitation assays using VHL and a panel of point mutants of HIF 1alpha in this region , as well as MS and in vitro binding assays , we now provide evidence that this modification , which occurs under normoxic conditions , is hydroxylation of Pro 564 of HIF 1alpha . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Taken together with our previous Cul 2 mutation analysis these data suggest that development of sporadic and familial RCC is not commonly contributed to by genetic events altering the destruction domain of HIF 1alpha , or components of the HIF alpha destruction complex other than VHL itself . ^^^ The pVHL associated SCF ubiquitin ligase complex : molecular genetic analysis of elongin B and C , Rbx 1 and HIF 1alpha in renal cell carcinoma . ^^^ Two amino acid substitutions ( Pro582Ser and Ala588Thr ) were identified in the oxygen dependent degradation / pVHL binding domain of HIF 1alpha , however neither substitution was observed exclusively in tumour samples . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| In these cells , defects in ubiquitylation of exogenous human HIF 1alpha in vitro could be complemented by wild type pVHL , and re expression of a wild type VHL gene restored a normal pattern of HIF / HRE activity , demonstrating the critical dependence of HIF regulation on pVHL in CHO cells . ^^^ In contrast , other mutant cells had no demonstrable mutation in the VHL gene , and ubiquitylated exogenous HIF 1alpha normally , suggesting that they contain defects at other points in the oxygen regulated processing of HIF alpha subunits . . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The decreased HIF 1alpha expression was not dependent on VHL interaction because a renal carcinoma cell line with VHL mutation and constitutive high HIF 1alpha expression also showed down regulation of HIF 1alpha after treatment with LY 294002 . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| FIH 1 : a novel protein that interacts with HIF 1alpha and VHL to mediate repression of HIF 1 transcriptional activity . ^^^ O ( 2 ) dependent binding of the von Hippel Lindau ( VHL ) tumor suppressor protein targets the HIF 1alpha subunit for ubiquitination and proteasomal degradation . ^^^ In addition , we demonstrate that FIH 1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF 1alpha transactivation function by recruiting histone deacetylases . ^^^ Involvement of VHL in association with FIH 1 provides a unifying mechanism for the modulation of HIF 1alpha protein stabilization and transcriptional activation in response to changes in cellular O ( 2 ) concentration . . ^^^ |
|
| Interacting proteins: Q16665 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 . ^^^ In pVHL defective cells this process is blocked leading to constitutive up regulation of HIF 1alpha subunits , activation of the HIF complex and overexpression of HIF target genes . ^^^ Equally regulation of the HIF 1alpha / pVHL interaction in normal cells should provide insights into the physiological mechanisms operating in cellular oxygen sensing . . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| It has recently been shown that HIF alpha undergoes an iron and oxygen dependent modification before it can interact with pVHL , and that this results in hydroxylation of at least one prolyl residue ( HIF 1alpha , Pro 564 ) . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| We further investigated the effect of NO on the binding activity of the von Hippel Lindau tumor suppressor protein ( pVHL ) to the N terminal activation domain ( NAD ) overlapping the oxygen dependent degradation domain ( ODD ) of HIF 1alpha , because this reaction involves prolyl hydroxylation in NAD that requires oxygen . ^^^ |
|
| Interacting proteins: Q16665 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 . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Leu 574 of HIF 1alpha is essential for the von Hippel Lindau ( VHL ) mediated degradation pathway . ^^^ In particular , the von Hippel Lindau ( VHL ) protein complex , an E 3 ubiquitin ligase , binds to the ODD upon hydroxylation of HIF 1alpha Pro 564 . ^^^ Moreover , we demonstrate that Leu 574 of HIF 1alpha is essential for VHL binding to the C terminal ODD . ^^^ Taken together , this study provides new insight into the mechanisms underlying VHL mediated HIF 1alpha degradation and transcriptional activation , and a molecular basis for drug targeting . . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Recently , prolyl hydroxylation was identified as a key regulatory event that targets the HIF 1alpha subunit for proteasomal degradation via the pVHL ubiquitination complex . ^^^ We present further evidence showing that ARD 1 mediated acetylation enhances interaction of HIF 1alpha with pVHL and HIF 1alpha ubiquitination , suggesting that the acetylation of HIF 1alpha by ARD 1 is critical to proteasomal degradation . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The stability and activity of HIF 1alpha are regulated by the interaction with various proteins , such as pVHL , p 53 , and p300 / CBP as well as by post translational modifications , hydroxylation , acetylation , and phosphorylation . ^^^ ARD 1 acetylates HIF 1alpha and stimulates pVHL mediated ubiquitination of HIF 1alpha . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The mechanism by which hypoxia induces gene transcription involves the inhibition of hypoxia inducible factor ( HIF ) 1alpha prolyl hydroxylase activity , which prevents von Hippel Lindau ( vHL ) dependent targeting of HIF 1alpha to the ubiquitin proteasome pathway . ^^^ |
|
| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Here , we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF 1alpha , its negative regulator VHL , and a known downstream target , VEGF . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| PX 12 and pleurotin also decreased HIF 1alpha protein levels and HIF 1 trans activation in RCC 4 renal cell carcinoma cells that constitutively overexpress HIF 1alpha protein because of loss of the pVHL gene , indicating that HIF 1alpha is inhibited independently of the pVHL pathway . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Interestingly , and in contrast to established hypoxic signaling concepts , TNF alpha elicited HIF 1alpha accumulation in a ubiquitinated form that still bound the von Hippel Lindau ( pVHL ) protein . ^^^ These data indicate that HIF 1alpha accumulation by TNF alpha demands the NF kappaB pathway , preserves ubiquitination of HIF 1alpha , and allows the HIF 1alpha pVHL interaction . . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| To examine the effects of growth factors and cytokines on histone acetylation and levels of p 53 , VHL and HIF 1alpha , the rat intestinal epithelial cell line IEC 6 was treated with epidermal growth factor ( EGF ) and interleukin ( IL ) 15 for 35 days . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Indeed , GSNO as well as the hypoxia mimic CoCl 2 decreased ubiquitination of HIF 1alpha and GSNO induced HIF 1alpha failed to coimmunoprecipitate with pVHL ( von Hippel Lindau protein ) . ^^^ Considering that HIF 1alpha pVHL interactions require prolyl hydroxylation of HIF 1alpha , we went on to demonstrate inhibition of HIF 1alpha prolyl hydroxylases ( PHDs ) by GSNO . ^^^ In vitro HIF 1alpha pVHL interactions revealed that GSNO dose dependently inhibits PHD activity but not the interaction of a synthetic peptide resembling the hydroxylated oxygen dependent degradation domain of HIF 1alpha with pVHL . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Although the Pro582Ser polymorphism is located in the ODD domain of HIF 1alpha it does not diminish the association of HIF 1alpha with VHL . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Nevertheless , large tumors completely regressed in response to intratumoral injection of a combination of antisense HIF 1alpha and VHL plasmids . ^^^ These novel results suggest that synergistic therapies that simultaneously block the expression or function of HIF 1alpha , and enhance the expression or function of VHL may be beneficial in the treatment of cancer . . ^^^ In the present study , we sought to determine whether engineered overexpression of pVHL in tumors other than RCC can inhibit tumor growth , either as a monotherapy , or in combination with antisense HIF 1alpha therapy . ^^^ Intratumoral injection of subcutaneous EL 4 thymic lymphomas with an expression plasmid encoding pVHL resulted in the downregulation of HIF 1alpha and vascular endothelial growth factor ( VEGF ) . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| HBx directly interacted with the bHLH / PAS domain of HIF 1alpha but not with the von Hippel Lindau protein ( pVHL ) . ^^^ HBx decreased the binding of pVHL to HIF 1alpha and prevented ubiquitin dependent degradation of HIF 1alpha . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Furthermore , seven of the 13 ( 53 . 8 % ) VHL mutants immunohistochemically showed high HIF 1alpha expression . ^^^ The mean percentage of cells with strong cytoplasmic HIF 1alpha expression was 67 . 5 % in tumors with VHL mutations , and this level was significantly higher than that in tumors without mutations ( 50 . 8 % , P < 0 . 05 ) . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| RAS kidneys also showed tissue fibrosis ( by trichrome and Sirius red staining ) , increased superoxide anion abundance , NAD ( P ) H oxidase , VHL protein , and HIF 1alpha mRNA expression . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Expression of the von Hippel Lindau ( VHL ) tumor suppressor factor blocked the expression of both FECH mRNA and HIF 1alpha protein during normoxic culture of renal carcinoma cell line ( RCC 4 ) . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| We demonstrate that in human granulosa lutein cells the tumor suppressor genes RB 1 , VHL , NF 1 , NF 2 , Wt 1 , p 53 , and APC and the hypoxia dependent transcription factors HIF 1alpha , 2alpha , and 3alpha are expressed . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Therefore , we have investigated a series of proteins , known to be involved in angiogenesis , including von Hippel Lindau protein ( pVHL ) , hypoxia inducible factor 1a ( HIF 1a ) , vascular endothelial growth factor ( VEGF ) , fetal liver kinase 1 ( Flk 1 ) , and endothelial and inducible nitric oxide synthase ( eNOS , iNOS ) by immunohistochemistry on paraffin embedded lung tissue of CDH patients ( n = 13 ) , patients with lung hypoplasia due to other causes ( n = 20 ) , and normal controls ( n = 33 ) . pVHL was expressed more frequently in the arterial smooth muscle cells of CDH lungs compared with both other groups . ^^^ Our data suggest a role for pVHL and HIF 1a in normal and abnormal pulmonary angiogenesis . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| These results suggest a mechanistic link between SDH mutations and HIF 1alpha induction , providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations . . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The half life of the HIF 1alpha subunit is determined by oxygen dependent prolyl hydroxylation , which is required for binding of the von Hippel Lindau protein ( VHL ) , the recognition component of an E 3 ubiquitin ligase that targets HIF 1alpha for ubiquitination and degradation . ^^^ OS 9 gain of function promotes HIF 1alpha hydroxylation , VHL binding , proteasomal degradation of HIF 1alpha , and inhibition of HIF 1 mediated transcription . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| VHL protein interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF 1alpha . ^^^ Here , we show that pVHL interacting deubiquitinating enzyme 2 , VDU 2 , but not VDU 1 , interacts with HIF 1alpha . ^^^ Although pVHL functions as a master control for HIF 1alpha stabilization , as pVHL E 3 ligase mediates the ubiquitination of both HIF 1alpha and VDU 2 , the balance between the pVHL mediated ubiquitination and VDU 2 mediated deubiquitination of HIF 1alpha provides another level of control for HIF 1alpha stabilization . . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Enzymes of this class , such as prolyl 4 hydroxylases , mediate the oxygen and iron dependent degradation of the hypoxia inducible factor HIF 1alpha , which requires the E 3 ubiquitin ligase activity of pVHL . ^^^ Considering that the pathways for IRP 2 and HIF 1alpha degradation share remarkable similarities , we investigated whether pVHL may also be involved in the degradation of IRP 2 . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| When oxygen levels are high , the HIF 1alpha subunit is hydroxylated and is targeted for degradation by the von Hippel Lindau tumor suppressor protein ( VHL ) . ^^^ This regulatory pathway is evolutionarily conserved , and the Caenorhabditis elegans hif 1 and vhl 1 genes encode homologs of the HIF 1alpha subunit and VHL . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The von Hippel Lindau protein ( pVHL ) is a major tumor suppressor protein and also associated with the inhibition of angiogenesis via HIF 1alpha ubiquitination and proteasomal degradation . ^^^ Furthermore , Tid 1 ( L ) protein ; enhanced the interaction between HIF 1alpha and pVHL , leading to the destabilization of HIF 1alpha protein ; therefore , Tid 1 ( L ) protein decreased vascular endothelial growth factor expression and inhibited angiogenesis in vivo and in vitro . ^^^ These findings propose that Tid 1 ( L ) may play a critical role in pVHL mediated tumor suppression by modulating the pVHL dependent HIF 1alpha stability . . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| We investigated the genetic changes in the VHL gene and HIF 1alpha and studied their clinical implications in patients with sporadic CC RCC . ^^^ Polymerase chain reaction single strand conformation polymorphism analysis was performed to detect VHL mutations and genetic changes in HIF 1alpha , which were followed by automated direct sequencing . ^^^ However , it suggests that the therapeutic and prognostic implication of somatic VHL alteration may be different according to the mutational subtype and that the Pro582Ser change in HIF 1alpha may contribute to the development of metastases . . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The effect of the SD was dependent on Pro 564 since a mutated SD , in which Pro 564 had been replaced by a glycine residue , failed to bind the von Hippel Lindau protein ( pVHL ) and to stabilise HIF 1alpha . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| By using the von Hippel Lindau ( pVHL ) HIF 1alpha capture assay , we went on to demonstrate binding of pVHL to HIF 1alpha under DFX / NO but not DFX alone . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| In the presence of oxygen and iron , hypoxia inducible factor ( HIF 1alpha ) is rapidly degraded via the prolyl hydroxylases ( PHD ) / VHL pathways . ^^^ Although hypoxia / DFX induced PHD 3 , we excluded the PHD / VHL pathway in the regulation of HIF 1alpha under hypoxia / DFX . ^^^ Under normoxia , HIF 1alpha is degraded via the classic PHD / VHL pathway , is expressed at low levels and therefore does not activate the feedback loop . ^^^ But under hypoxia , HIF 1alpha accumulates and transcriptionally activates its own degradation that is independent from the PHD / VHL pathway . . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Recent studies have shown that a protein known as CSN 5 or JAB 1 interacts with both the HIF 1alpha oxygen responsive transcription factor and its oxygen dependent regulator , the Von Hippel Lindau ( pVHL ) tumor suppressor . ^^^ The exact function of the CSN 5 interaction with pVHL and HIF 1alpha remains to be fully elucidated , but it is clear that the interaction is both oxygen dependent and that CSN 5 may play different roles under oxic and hypoxic responses . ^^^ Further , evidence has also been published indicating that pVHL can be potentially post translationally modified by CSN 5 ( de neddylation ) and that CSN 5 transcription is regulated by hypoxia as are many of the key pVHL / HIF 1alpha regulatory genes such as the PHDs and OS 9 . ^^^ This review will give a broad overview of known CSN 5 and COP 9 Signalosome functions and how these functions impact the pVHL / HIF 1alpha signaling complex and potentially other oxygen sensitive response networks . . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| HIF 1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene , VHL , which targets HIF 1alpha degradation . ^^^ |
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| Interacting proteins: Q16665 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 . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| In addition , we document direct HIF 1alpha binding to the VHL promoter and identify a functional hypoxia response element ( HRE ) within the VHL promoter . ^^^ Here , we report that pVHL itself is induced in prolonged hypoxia in a kinetic that parallels the observed downregulation of HIF 1alpha protein under such conditions . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Some of these results indicate that seal HIF 1alpha protein can bind HIF Ibeta , DNA , transcriptional coactivators , and von Hippel Lindau protein ( pVHL ) . ^^^ The presence of HIF 1alpha in seal tissues was not related to the absence of pVHL , which was found to be present in all seal tissues examined . ^^^ 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 . ^^^ |
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| Interacting proteins: Q16665 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: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Furthermore , we determined , for the first time , that EGCG inhibits prolyl hydroxylation of HIF 1alpha , thus preventing HIF 1alpha and pVHL interaction . . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The alpha subunit of HIF factor 1 ( HIF 1 ) contains two highly conserved oxygen dependent degradation domains ( 402 ODD and 564 ODD ) , each of which includes a proline that is hydroxylated in the presence of oxygen , allowing the von Hippel Lindau ( VHL ) E 3 ubiquitin ligase to interact and target HIF 1alpha to the proteasome for degradation . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Hydroxylation of HIF 1alpha by prolyl hydroxylases ( PHDs ) recruits the von Hippel Lindau ( pVHL ) E 3 ubiquitin ligase complex to initiate proteolytic destruction of the alpha subunit . ^^^ By using a HIF 1alpha pVHL binding assay , we show that NO released from DETA NO restored prolyl hydroxylase activity under hypoxia . ^^^ In vitro HIF 1alpha pVHL interaction assays demonstrated that low level ROS formation increased prolyl hydroxylase activity , an effect antagonized by ROS scavengers . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The von Hippel Lindau tumor suppressor protein VHL is a component of a ubiquitin ligase promoting proteolysis of HIF 1alpha . ^^^ By using a genetic approach , we have demonstrated the essential role of the hypoxia / VHL / HIF 1alpha pathway in endochondral bone development . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| It results from a Von Hippel Lindau ( VHL ) gene mutation ( C598T ) that causes increased HIF 1alpha activity and erythrocyte production in the face of normoxia . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Consistent with these results , type 2A but not type 2B mutant VHL proteins retained significant ubiquitin ligase activity towards HIF 1alpha in vitro . ^^^ Renal cell carcinoma risk in type 2 von Hippel Lindau disease correlates with defects in pVHL stability and HIF 1alpha interactions . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Because pVHL ( von Hippel Lindau protein ) directs the proteolysis of Hif 1alpha under `` normoxic ' ' conditions , we achieved constitutive stabilization of Hif 1alpha through thymic deletion of Vhlh and reversed Hif 1alpha stabilization with double deletion of Vhlh and Hif 1alpha . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The mechanism for the significant stabilization and elevation of HIF 1alpha protein which drives these other parameters was previously shown by us and others to involve a loss of cellular Fe as well as inhibition of HIF 1alpha dependent prolyl hydroxylases which target the binding of VHL ubiquitin ligase and degrade HIF 1alpha . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Dominant negative N17Rac1 and N17Cdc42 could upregulate the expression of p 53 and pVHL but downregulate that of HIF 1alpha and VEGF under hypoxia . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Degradation of HIF 1alpha requires association of the von Hippel Lindau protein ( pVHL ) to provoke ubiquitination followed by proteasomal digestion . ^^^ To understand the role of NO under hypoxia we made use of pVHL deficient renal carcinoma cells ( RCC 4 ) that show a high steady state HIF 1alpha expression under normoxia . ^^^ An active role of calpain in lowering HIF 1alpha amount was also evident in pVHL containing human embryonic kidney cells when the calcium pump inhibitor thapsigargin reduced HIF 1alpha that was stabilized by the prolyl hydroxylase inhibitor dimethyloxalylglycine ( DMOG ) . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Immunohistochemically , markers implicated in VHL associated neoplasia , including HIF 1alpha , inhibin , and Melan A ( in clear cell PENs ) and MUC 6 ( in serous cystadenomas ) were mostly negative in lipid rich PENs ( 1 of 10 , 1 of 10 , 0 of 10 and 0 of 10 , respectively ) . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Loss of E cadherin expression and decreased cell cell adhesion in VHL null RCC 4 cells were corrected by enforced expression of VHL , a dominant negative HIF 1alpha mutant , or a short hairpin RNA directed against HIF 1alpha . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| In addition to its regulation by oncogenes or tumor suppressor genes such as HER 2 , p 53 , VHL , and PTEN , overexpression of HIF 1alpha is induced by hypoxia . ^^^ |
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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| Thus , by using a novel conditional VHL knockout mouse model , we could show that the VHL gene plays an important role in the developing vasculature and liver during embryogenesis through regulation of HIF 1alpha and its target genes . ^^^ |
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| Interacting proteins: Q16665 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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| Interacting proteins: Q16665 and P40337 |
Pubmed |
SVM Score :0.0 |
| The von Hippel Lindau ( VHL ) tumor suppressor protein is a component of a ubiquitin ligase promoting proteolysis of HIF 1alpha . ^^^ By using a genetic approach , we have demonstrated that VHL and HIF 1alpha are critical regulators of endochondral bone development . . ^^^ |
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