ライフサイエンスコーパス: pVHL

1 ex containing the von Hippel-Lindau protein (pVHL).

2 stably expressing the wild-type VHL protein (pVHL).

3 finity binding to Von Hippel-Lindau protein (pVHL).

4 von Hippel-Landau tumour suppressor protein (pVHL).

5 n of the von Hippel-Lindau tumor suppressor (pVHL).

6 k is regulated by von Hippel-Lindau protein (pVHL).

7 ng c-src-mediated proteosomal degradation of pVHL.

8 e constitutively activated in the absence of pVHL.

9 ibly via direct binding and stabilization of pVHL.

10 esting a potential link between U19/Eaf2 and pVHL.

11 the CTD allows the interaction of Rpb1 with pVHL.

12 omains is the least stable region in unbound pVHL.

13 teolytic degradation by the VHL gene product pVHL.

14 ts in the von Hippel-Lindau tumor suppressor pVHL.

15 hat is stabilized by direct interaction with pVHL.

16 SPARC) and all were upregulated by wild-type pVHL.

17 er of the von Hippel-Lindau tumor suppressor pVHL.

18 -Lindau (VHL) tumor suppressor gene product, pVHL.

19 regard to post-transcriptional regulation of pVHL.

20 nvasion and metastasis through its effect on pVHL.

21 reinstates the interaction of HIF-1alpha and pVHL.

22 ndidate renal tumor suppressor stabilized by pVHL.

23 n of c-src and subsequent destabilization of pVHL.

24 of Spry2 and abrogated its interactions with pVHL.

25 the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment w

26 These results demonstrate that pVHL acts to promote BIM(EL) protein stability in RCC ce

27 In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tum

28 Domain mapping analysis showed that the pVHL alpha-domain and the RACK1 WD 6-7 domains are criti

29 Overexpression of pVHL also increased activation of focal adhesion kinase

30 pVHL also reduced the stability of IGF1R mRNA via seques

31 pVHL also ubiquitylates the large subunit of RNA polymer

32 l staining revealed reduced concentration of pVHL and accumulation of KLF4 in breast cancer tissues.

33 he HIF binding site was shown to destabilize pVHL and decrease its binding affinity to HIF.

34 This interaction between pVHL and HIF is governed by post-translational prolyl hy

35 xia; thus, we set out to investigate whether pVHL and HIF participate in the hypoxia-mediated degrada

36 Codeletion of pVHL and HIF-2alpha in JG cells completely prevented the

37 munohistochemical staining revealed elevated pVHL and reduced KLF4 levels in colon cancer tissues.

38 ts suggest that specific association between pVHL and the hydroxylated HIF-alpha requires both the L1

39 proliferation of fibroblasts overexpressing pVHL and those cells were more resistant to the inhibiti

40 Von Hippel Lindau protein (pVHL) and hypoxia inducible factor (HIF) are key mediato

41 ygen requires the protein von Hippel-Lindau (pVhl) and pVhl disruption results in constitutive Hif ac

42 von Hippel-Lindau tumor suppressor protein (pVHL) and the hypoxia inducible factor (HIF) transcripti

43 al epithelium, emphasizing the importance of pVHL as a controller of mitotic fidelity in vivo.

44 U19/Eaf2 stabilizes pVHL, as shown by protein stability and pulse-chase stud

45 We identified Von Hippel-Lindau, pVHL, as the protein that governs KLF4 turnover in breas

46 Therefore, we named this protein pVHL-associated KRAB-A domain-containing protein (VHLaK)

47 that Spry2 acts as a scaffold to bring more pVHL/associated E3 ligase in proximity of HIF1alpha and

48 consensus destruction (D) box sequences, and pVHL associates with Cdh1, an activator of the anaphase-

49 We found that pVHL associates with the NF-kappaB agonist Card9 but doe

50 D domain of HIF-2alpha that are required for pVHL binding prevented the binding of cobalt and stabili

51 We establish that pVHL binds to Tat-binding protein-1 (TBP-1), a component

52 The von Hippel-Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited A

53 d was suppressed by full-length VHL protein (pVHL) but only partially by truncated VHL lacking the Sp

54 In cells with suppression of pVHL by short hairpin RNA, the Na-K-ATPase was not degra

55 These results demonstrate that a loss of pVHL can induce growth arrest in certain cells types, wh

56 pVHL can recruit VHLaK to repress HIF-1alpha transcripti

57 Therefore pVHL can serve as an adaptor for both a ubiquitin conjug

58 nctions of the VHL tumor suppressor protein (pVHL) can contribute to tumor initiation and progression

59 alpha levels in normoxia and hypoxia in both pVHL-competent and -deficient cells, whereas HAF knockdo

60 pVHL competes with IGF-I receptor (IGF-IR) for binding t

61 pVHL confers substrate specificity to the E3 ligase comp

62 oteins is essential for their recognition by pVHL containing ubiquitin ligase complexes and subsequen

63 pVHL contains consensus destruction (D) box sequences, a

64 However, it is unknown whether pVHL contributes to pulmonary fibrosis.

65 destabilization of BIM(EL) in the absence of pVHL contributes to the increased resistance of VHL-null

66 von Hippel-Lindau tumour suppressor protein (pVhl) controls hypoxia-inducible transcription factor (H

67 Loss of Jade-1 stabilization by pVHL correlates with renal cancer risk, making the relat

68 The interaction of Jade-1 and pVHL correlates with renal cancer risk.

69 pVHL-defective clear cell renal cell carcinoma cell line

70 nical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-

71 portant role in promoting tumor formation by pVHL-defective renal carcinoma cells among the three HIF

72 pVHL-defective renal carcinoma cells exhibit increased N

73 targets IGBP3 and PAI-1 are overproduced by pVHL-defective renal carcinoma cells.

74 a indicate that HIF plays a critical role in pVHL-defective tumor formation, raising the possibility

75 Decreased clusterin secretion by pVHL-defective tumors was confirmed in vivo by immunohis

76 Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activit

77 In pVHL-deficient cells, hypoxia did not decrease the Na-K-

78 tively activated in and drives the growth of pVHL-deficient clear cell RCCs.

79 at conditional inactivation of Hif-2alpha in pVHL-deficient mice suppressed hepatic Epo and the devel

80 pVHL-deficient RCC cells also demonstrate elevated PI3K/

81 Upon IGF-I stimulation, pVHL-deficient RCC cells exhibit increased RACK1/IGF-IR

82 Importantly, pVHL-deficient RCCs are dependent upon JNK activity for

83 pendent JNK hyperactivation is unique to the pVHL-deficient state.

84 nding regulator TRAP, and the hypoxia factor pVHL define a recognition module for peptides and nuclei

85 D box-independent pVHL degradation was also detected, indicating that othe

86 her ubiquitin ligases are also activated for pVHL degradation.

87 of HIF1alpha by a von Hippel-Lindau protein (pVHL)-dependent mechanism.

88 STRA13 is a pVHL-dependent bHLH transcription factor up-regulated on

89 tes HIF-1alpha prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1alpha.

90 enhancing HIF-1alpha hydroxylation and thus pVHL-dependent degradation of HIF-1alpha.

91 BP-1 promotes degradation of Hif1 alpha in a pVHL-dependent manner that requires the ATPase domain of

92 e factor 1alpha and 2alpha, tagging them for pVHL-dependent polyubiquitination and proteasomal degrad

93 insights into KLF4 degradation and show that pVHL depletion in colorectal cancer cells leads to cell-

94 Overexpression of pVHL did not alter hypoxia-inducible factor luciferase r

95 Experimentally, type 2B pVHL disease mutant Y98N at the HIF binding site was sho

96 res the protein von Hippel-Lindau (pVhl) and pVhl disruption results in constitutive Hif activation.

97 observed that the interface between the two pVHL domains is the least stable region in unbound pVHL.

98 d with PHD1-3 and von Hippel-Lindau protein (pVHL) during normoxia but not in hypoxia.

99 y correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways.

100 ation of Na-K-ATPase required the functional pVHL E3 ligase and Ubc5 since pVHL mutants and dominant-

101 ) of HIF-1alpha trigger its association with pVHL E3 ligase complex, leading to HIF-1alpha degradatio

102 beta-domains responsible for assembling the pVHL E3 ubiquitin ligase complex and for recognizing the

103 xylase mediated hydroxylation and subsequent pVHL-elicited ubiquitylation of Spry2 target it for degr

104 ding sites, successfully stabilized the Y98N pVHL-elongin C complex and lowered the binding free ener

105 However, it is unclear whether pVHL exerts these mitotic regulatory functions in vivo a

106 Directly inhibiting BIM(EL) expression in pVHL-expressing RCC cells caused a similar decrease in c

107 induced cell cycle arrest is associated with pVHL expression in RCC cells.

108 e RACK1 expression level is not regulated by pVHL expression status, suggesting that pVHL modifies RA

109 Suppressing pVHL expression with RNA interference resulted in a decr

110 G1, Cdh1 downregulation results in increased pVHL expression, whereas Cdh1 overexpression results in

111 eas Cdh1 overexpression results in decreased pVHL expression.

112 t on PLD in renal cancer cells with restored pVHL expression.

113 ted that estrogen-induced down-regulation of pVHL facilitates accumulation of KLF4.

114 /Eaf2 and both the alpha and beta domains of pVHL for this binding.

115 pVHL forms a ternary complex with elongin C and elongin

116 pVHL forms part of the E3 ubiquitin ligase complex that

117 ked to classical VHL disease compromise this pVHL function although some missense mutations result in

118 serves as a direct mediator between loss of pVHL function and enhanced IGF-IR signaling pathway in R

119 er, although the effects of this mutation on pVHL function are not fully understood.

120 n hypoxia-inducible factor (HIF)-independent pVHL function formed the basis for selectivity.

121 Loss of pVHL function in this VHL conditional knockout mouse mod

122 ear to function cooperatively with a loss of pVHL function in tumorigenesis.

123 losteric effects of these mutants may rescue pVHL function in von Hippel-Lindau disease.

124 ible factor (HIF)-alpha subunits and loss of pVHL function leads to HIF stabilization.

125 The significance for pVHL function of two further genes upregulated by wild-t

126 Loss of pVHL function results in constitutive activation of HIF-

127 n is a secreted marker for a HIF-independent pVHL function that might be especially important in pheo

128 tially compared with isogenic cells in which pVHL function was restored.

129 (as a result of kidney-specific ablation of pVHL function) were reverted in vivo also by genetic inh

130 cells related to: tumor suppressor protein (pVHL) function, the histone acetylation dependence upon

131 The protein pVHL functions in a multi-subunit E3 ubiquitin ligase th

132 rting the novel and intriguing findings that pVHL has a crucial role in endochondral bone development

133 We show that pVHL has a decreased half-life in G1, Cdh1 downregulatio

134 ng in VHL disease and can be rationalized if pVHL has functions separate from its control of HIF.

135 The VHL protein (pVHL) has been implicated in many cellular activities in

136 The VHL gene product, pVHL, has multiple functions including directing the pol

137 In the absence of pVHL, HIF becomes stabilized and is free to induce the e

138 the coordination of internal motions of the pVHL.HIF-1alpha complex.

139 Moreover, dynamic organization of pVHL.HIF-1alpha recognition is focally centered on Gln(1

140 We recently reported inhibitors of the pVHL:HIF-1alpha interaction, however they exhibited mode

141 We found that in the presence of pVHL hypoxia decreased Na-K-ATPase activity and promoted

142 yltransferase activity that is stabilized by pVHL in a manner that correlates with risk of VHL renal

143 en together, our findings support a role for pVHL in elevating p53 expression, implicate HuR in enhan

144 ients with IPF expressed increased levels of pVHL in fibroblastic foci.

145 alpha is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells.

146 Bleomycin treatment also induced pVHL in lung fibroblasts, but not in alveolar type II ce

147 ta provide direct evidence for a key role of pVHL in mediating oriented cell division and faithful mi

148 e found that renin cell-specific deletion of pVHL in mice leads to a phenotype switch in JG cells, fr

149 Mice lacking pVHL in osteoblasts with constitutive HIF-1alpha activat

150 Although the involvement of pVHL in oxygen sensing through targeting hypoxia-inducib

151 We thus propose that suppression of pVHL in response to estrogen signaling results in elevat

152 In order to investigate the role of pVhl in T-cell development, we generated mice with thymo

153 Inactivation of pVhl in the mouse germ line results in embryonic lethali

154 key regulatory role for the tumor suppressor pVHL in the regulation of the vascular system and normal

155 t deletion of the von Hippel-Lindau protein (pVHL) in juxtaglomerular (JG) cells of the kidney suppre

156 pha proteins, and von Hippel-Lindau protein (pVHL) in mouse folic acid nephropathy, a model in which

157 ion of the wild-type protein encoded by VHL (pVHL) in tumors with biallelic VHL inactivation (VHL(-)(

158 tween the elongin C and HIF binding sites in pVHL, in the alpha- and beta-domains, respectively, medi

159 proteins, Skp2, Fbw7, beta-TrCP1, Cdc4, and pVHL, in two forms: bound to their substrates and bound

160 ncluding DOC-2/DAB2 and MLC2) the effects of pVHL inactivation and hypoxia were similar.

161 erally in renal cancer, perhaps initially by pVHL inactivation and subsequently by increased proteaso

162 o investigate the functional consequences of pVHL inactivation and the role of HIF signaling in renal

163 herefore, the pathological changes caused by pVHL inactivation in skin and liver are due largely to d

164 pVHL inactivation results in stabilization of the hypoxi

165 e closely phenocopied the changes seen after pVHL inactivation than did the HIF2alpha variant alone.

166 Hippel-Lindau tumor suppressor gene product (pVHL), including targeting the alpha subunits of the het

167 In addition, cells lacking wild-type pVHL, including cells producing type 2C pVHL mutants, we

168 Silencing of pVHL increased levels of Spry2 by decreasing its ubiquit

169 Overexpression of pVHL increased lung fibroblast proliferation, protein ab

170 receptor 2 (PAR2) (both downregulated by wt pVHL) increased cell growth and motility in a RCC cell l

171 , indicating that full in vivo expression of pVHL indeed requires U19/Eaf2.

172 High CSN5 expression generates a pVHL-independent form of CSN5 that stabilizes HIF-1 alph

173 nd ubiquitinates HIF-1alpha by an oxygen and pVHL-independent mechanism, thus targeting HIF-1alpha fo

174 f2 knockout mice expressed reduced levels of pVHL, indicating that full in vivo expression of pVHL in

175 In addition, overexpression of pVHL induced expression of the alpha5 integrin subunit.

176 ting its mRNA expression, and overexpressing pVHL inhibited BIM(EL) polyubiquitination.

177 for activated C kinase 1 (RACK1) is a novel pVHL-interacting protein.

178 ion and resultant von Hippel-Lindau protein (pVHL) interactions in the ubiquitin-proteasome-mediated

179 Furthermore, reintroducing pVHL into RCC cells increased endogenous Jade-1 and supp

180 Reintroducing pVHL into VHL-null cells increased the half-life of BIM(

181 Under native conditions, free pVHL is a molten globule, but it is stabilized in the E3

182 Taken together, these results suggest that pVHL is a novel substrate of APC/C(Cdh1).

183 The von Hippel-Lindau tumor suppressor pVHL is an E3 ligase that targets hypoxia-inducible fact

184 Hippel-Lindau (VHL) tumor suppressor protein pVHL is commonly mutated in clear cell renal cell carcin

185 The von Hippel-Lindau (VHL) tumor suppressor pVHL is lost in the majority of clear-cell renal cell ca

186 that were highly similar to those seen when pVHL is lost in these organs.

187 Loss of pVHL is not sufficient, however, to cause ccRCC.

188 Type 2B mutant pVHL is predicted to be defective in hypoxia inducible f

189 a suggest that tight regulation of Hif-1 via pVhl is required for normal thymocyte development and vi

190 One function of pVHL is to regulate the stability of the hypoxia-inducib

191 von Hippel Lindau tumor suppressor protein (pVHL) is a component of a ubiquitin ligase that promotes

192 The von Hippel-Lindau tumor suppressor (pVHL) is a component of an E3 ubiquitin ligase and targe

193 von Hippel-Lindau tumor-suppressor protein (pVHL) is associated with von Hippel-Lindau disease, an i

194 tumor suppressor von Hippel-Lindau protein (pVHL) is critical for cellular molecular oxygen sensing,

195 von Hippel-Lindau tumor suppressor protein (pVHL) is frequently mutated in kidney cancer and is part

196 von Hippel-Lindau tumor suppressor protein (pVHL) is one of these proteins.

197 The VHL tumor suppressor protein (pVHL) is part of an E3 ubiquitin ligase that targets HIF

198 The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3

199 ippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor

200 n of the von Hippel-Lindau tumor suppressor, pVHL, is associated with both hereditary and sporadic re

201 The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets

202 The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin

203 B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases

204 SB1 protein level negatively correlates with pVHL level and metastasis-free survival in clinical samp

205 We found that pVHL levels decreased in hypoxia and that hypoxia-induce

206 pVHL levels fluctuate during the cell cycle, paralleling

207 ell differentiation in 20% O2; additionally, pVHL levels were modulated during the same time period.

208 Deprived of pVhl, livers accumulated tryglicerides and circulating k

209 the combined loss of Phd2 and Phd3 resembles pVHL loss appear to differ for different HIF-responsive

210 und that Ror2 was indeed associated with the pVHL loss in RCC as well as with VHL somatic mutations t

211 A multistep signaling pathway that links pVHL loss to JNK activation involves the formation of a

212 clear-cell RCC between PTEN inactivation and pVHL loss, which leads to decreased Jade-1 levels that s

213 target of the VHL ubiquitylating complex and pVHL may regulate angiogenesis by targeting hsRPB7 for d

214 roxylation and Ser5 phosphorylation of Rbp1, pVHL may regulate tumor growth.

215 -1 alpha-hydroxylated prolines involved with pVHL-mediated binding inhibits the observed FOXO4-mediat

216 (VHL(-)(/)(-)) suppresses tumorigenesis, and pVHL-mediated degradation of HIFalpha is necessary and s

217 pVHL-mediated degradation of Na-K-ATPase required the fu

218 1alpha), a protein typically regulated via a pVHL-mediated degradation pathway.

219 of reactive oxygen species was necessary for pVHL-mediated Na-K-ATPase degradation during hypoxia.

220 d by pVHL expression status, suggesting that pVHL modifies RACK1 functions independent of the VHL/elo

221 the functional pVHL E3 ligase and Ubc5 since pVHL mutants and dominant-negative Ubc5 prevented Na-K-A

222 pVHL mutants linked to familial pheochromocyctoma (type

223 sed vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by conco

224 type pVHL, including cells producing type 2C pVHL mutants, were defective with respect to expression

225 We have expressed missense pVHL mutations in Vhl(-/-) murine embryonic stem cells t

226 ut to investigate the potential influence of pVHL on protein translation.

227 of estrogen and show that elevated levels of pVHL or depletion of KLF4 attenuates the estrogen-induce

228 ell carcinoma (RCC) cells that either lacked pVHL or expressed pVHL through stable transfection were

229 These findings suggest that pVHL participates in the hypoxia-mediated degradation of

230 ort that the Von Hippel-Lindau gene product, pVHL, physically interacts with KLF4 and regulates its r

231 ese observations support the hypothesis that pVHL plays multiple roles in the cell, and that these ac

232 Moreover, suppression of pVHL prevented TGF-beta1-induced proliferation of mouse

233 hich the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, the

234 The sensitivity of pVHL-proficient cells to these shRNAs was not restored u

235 tion of HIFalpha or restoration of wild-type pVHL protein expression has not proved readily feasible,

236 The mechanism by which pVHL protein functions in renal tumor suppression remain

237 The polycystin-1 (PC1) and pVHL proteins may therefore participate in the same key

238 All mutant pVHL proteins restored proper hypoxic regulation of HIF1

239 l line expressing a Type 1 or Type 2B mutant pVHL (RCC-associated) to those of a Type 2A or 2C mutant

240 lyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells.

241 4 VHL-/- cells compared with their wild-type pVHL-reconstituted counterparts.

242 to coordinate dynamic coupling among distant pVHL regions, whose mutational disruption inactivates VH

243 Here we report that in RCC cells, pVHL regulates expression of Rpb1 and is necessary for l

244 pVHL regulates the protein stability of hypoxia-inducibl

245 The von Hippel-Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factor

246 pVHL regulation of CDKN1C, SPARC and GNG4 was not mimick

247 exogenous fibronectin, which indicates that pVHL regulation of fibronectin deposition plays an impor

248 as been well documented, less is known about pVHL regulation under both normoxic and hypoxic conditio

249 documented function of the VHL gene product (pVHL) relates to its ability to polyubiquitinate, and he

250 Introducing a pVHL-resistant hypoxia-inducible factor 1alpha (HIF1alph

251 interaction with von Hippel-Lindau protein (pVHL), resulting in HIF-1alpha degradation.

252 Loss of pVHL results in constitutive activation of the transcrip

253 results indicate that elevated expression of pVHL results in the aberrant fibronectin expression, act

254 ter gene assays, which further revealed that pVHL's inhibitory influence on protein synthesis occurre

255 This work reveals a new mechanism of pVHL's regulation by which cancer acquires invasiveness

256 -mediated p53 upregulation may contribute to pVHL's tumor suppressive functions in renal cell carcino

257 Instead, pVHL serves as an adaptor that promotes the phosphorylat

258 nal model, we show biochemical evidence that pVHL specifically binds the hyperphosphorylated Rpb1 in

259 Our simulations showed that the decrease in pVHL stability and binding affinity are allosterically r

260 x with elongin C and elongin B, critical for pVHL stability and function, which interacts with Cullin

261 We identified 30 differentially regulated pVHL targets (26 of which were 'novel') and the results

262 pVHL targets alpha subunits of the heterodimeric transcr

263 As the identification of novel pVHL targets might provide insights into pVHL tumour sup

264 The von Hippel-Lindau gene product (pVHL) targets the alpha subunit of basic helix-loop-heli

265 The von Hippel-Lindau (VHL) gene product, pVHL, targets the alpha subunit of the hypoxia-inducible

266 henocopy of the changes seen in mice lacking pVHL than the loss of Phd2 alone.

267 tatus of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1alpha degradation and

268 Second, in pVHL (the protein encoded by the VHL gene)-deficient ccR

269 ) cells that either lacked pVHL or expressed pVHL through stable transfection were used to prepare RN

270 protein 1 (WSB1) is a negative regulator of pVHL through WSB1's E3 ligase activity.

271 The VHL tumor suppressor protein (pVHL), through its oxygen-dependent polyubiquitylation o

272 hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation.

273 ions that directly compromise the ability of pVHL to assemble the E3 or to contact the substrate.

274 which promotes Card9 phosphorylation, links pVHL to control of NF-kappaB activity and tumorigenesis.

275 We first examined the ability of mutant pVHL to direct degradation of the hypoxia inducible fact

276 The binding of pVHL to HIFalpha requires that HIFalpha be hydroxylated

277 ur findings uncover a novel function for the pVHL tumor suppressor protein as regulator of protein tr

278 , binds both the CODD of HIF-1 alpha and the pVHL tumor suppressor.

279 hibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major und

280 vel pVHL targets might provide insights into pVHL tumour suppressor activity, we performed gene expre

281 t and HIF-independent mechanisms account for pVHL tumour suppressor activity.

282 These provide insights into mechanisms of pVHL tumour suppressor function and identify novel hypox

283 er, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulati

284 Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby

285 Because Spry2 can also associate with pVHL, using a mutant form of Spry2 (3P/3A-Spry2) that bi

286 We therefore propose that unexpectedly pVHL, via the degradation of KLF4, is a facilitating fac

287 Because pVHL (von Hippel-Lindau protein) directs the proteolysis

288 IF-1alpha is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal

289 f two further genes upregulated by wild-type pVHL was initially unclear, but re-expression of GNG4 (G

290 was a target of translational repression by pVHL was obtained from reporter gene assays, which furth

291 (3P/3A-Spry2) that binds HIF1alpha, but not pVHL, we show that WT-Spry2, but not the 3P/3A-Spry2 dec

292 Fibroblasts overexpressing pVHL were more sensitive to RGD peptide-mediated reducti

293 s showed an association between U19/Eaf2 and pVHL, whereas deletion mutagenesis revealed the requirem

294 he von Hippel-Lindau (VHL) tumor suppressor (pVHL), which inhibits ubiquitylation and degradation of

295 of HIF-1alpha is von Hippel-Lindau protein (pVHL), which mediates the oxygen-dependent, proteasomal

296 ions designed to stabilize unbound wild-type pVHL, which are away from the elongin C and HIF binding

297 control of AKT/AKT1 in RCC, through loss of pVHL, which decreases Jade-1 protein, or through attenua

298 on of the von Hippel-Lindau tumor suppressor pVHL, which targets both HIFs for proteasomal degradatio

299 mplex and lowered the binding free energy of pVHL with HIF.

300 This is initial evidence that pVHL, without any genetic alteration, can be regulated b