ライフサイエンスコーパス: FIH

1 FIH also catalyzes the hydroxylation of asparaginyl and

2 FIH deficiency alters immune composition in aged mice an

3 FIH has lower Km(app)(O2) values for the tested ARDs tha

4 FIH has multiple non-HIF substrates making it challengin

5 FIH is a non-heme Fe(II), alpha-ketoglutarate (alphaKG)-

6 FIH is an alpha-ketoglutatrate (alphaKG)-dependent, non-

7 FIH is an asparaginyl hydroxylase catalyzing post-transl

8 FIH is thus a potential target for adiposity control and

9 FIH-1 and Mint3 were both expressed in the NP and were s

10 FIH-1 interacts with two previously unknown partners, Pl

11 FIH-1 overexpression in HCEKs decreased AKT signaling, a

12 actor-inhibiting hypoxia-inducible factor 1 (FIH-1) diminished glycogen stores in vitro and in vivo,

13 actor inhibiting hypoxia-inducible factor 1 (FIH-1), we observed increases in epidermal DeltaNp63alph

14 actor-inhibiting hypoxia-inducible factor 1 (FIH-1); however, the biological significance of this phe

15 actor inhibiting hypoxia-inducible factor 1 (FIH-1; official symbol HIF1AN) is a hydroxylase that neg

16 actor inhibiting hypoxia-inducible factor-1 (FIH-1).

17 inhibiting hypoxia-inducible factor (HIF)-1 (FIH-1) is an asparaginyl beta-hydroxylase enzyme that wa

18 droxylase (PHD) and factor-inhibiting HIF-1 (FIH).

19 e identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1alpha and inhibits

20 nt the structure of factor-inhibiting HIF-1 (FIH-1), the pertinent asparaginyl hydroxylase involved i

21 controlled by factor inhibiting HIF-1alpha (FIH).

22 D) enzymes and factor-inhibiting HIF-1alpha (FIH-1), which regulate cellular HIF levels, and to study

23 ial is, in part, controlled through a miR-31/FIH-1 nexus.

24 ted with c-kit ligand to establish further a FIH-1/c-kit interaction via Western analysis.

25 ore, the structure reveals the presence of a FIH-1 homodimer that forms in solution and is essential

26 Consistent with a FIH-1/c-kit association, the diminished Akt signaling ob

27 ypoxia-inducible transcription factor HIF-a (FIH) and aspartate/asparagine-B-hydroxylase (AspH), cata

28 h Mint3 or the N terminus of Mint3 abrogated FIH-1-dependent reduction in HIF-1 activity under both n

29 Accordingly, FIH-1 increases epidermal growth factor receptor (EGFR)

30 ch identified a highly potent in vivo active FIH inhibitor, ZG-2291, the binding of which promotes a

31 ell death as the underlying mechanism for AD-FIH and suggest that the pharmacological manipulation of

32 ant familial isolated hypoparathyroidism (AD-FIH) is caused by a Cys --> Arg mutation (C18R) in the h

33 Additionally, FIH-1 regulates growth arrest and DNA damage-45 alpha (G

34 charge transfer transitions for (Fe+alphaKG)FIH indicated that these point mutations destabilized th

35 (Fe(II))FIH and (Fe(II)/alphaKG)FIH are found to be six-coordinate (6C), whereas (Fe(II)

36 harge transfer transition in (Fe(II)/alphaKG)FIH which is red-shifted upon CAD binding.

37 g (Notch), have been found to be alternative FIH targets, but the biologic relevance of this regulati

38 Although FIH tolerates a variety of chemically disparate residues

39 Although FIH-mediated hydroxylation of HIF-alpha is well characte

40 R endosomal trafficking and signaling, as an FIH-1 binding partner.

41 ARD protein with three ankyrin repeats is an FIH substrate, while more stable consensus ARD proteins,

42 ining whether a particular ARD protein is an FIH substrate; a consensus ARD protein with three ankyri

43 sequences for inhibiting PHD isoenzyme 2 and FIH were inserted into novel, nonviral, minicircle vecto

44 on, we investigated the role that miR-31 and FIH-1 play in regulating corneal epithelial glycogen.

45 time a potential connection between CDP and FIH that could lead to the development of future therape

46 PHD catalysis regulates HIFalpha levels, and FIH catalysis regulates HIF activity.

47 es, it is important to consider both PHD and FIH activity, and in the case of some sets of target gen

48 The expression of PHD and FIH and downstream target genes was assessed by quantita

49 d, combined application of selective PHD and FIH inhibitors resulted in the transcriptional induction

50 upregulation by double knockdown of PHD and FIH synergistically increases stem cell mobilization and

51 PHD and FIH were cloned from mouse embryonic stem cells.

52 2OG TCAIs as inhibitors of purified PHD2 and FIH.

53 nes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.

54 oxylase (broad spectrum), PHD-selective, and FIH-selective inhibitors, and investigated their effects

55 ses survivin (a key inhibitor of apoptosis), FIH targeting in HUVECs leads to selective repression of

56 Because FIH is a direct target of miR-31-5p, inhibition of miR-3

57 udy we investigated the relationship between FIH-1 and c-kit as it pertains to limbal and corneal epi

58 An inverse relationship between FIH-1 and c-kit signaling pathways accounts, in part, fo

59 d reversed the decrease in DeltaNp63alpha by FIH-1 depletion.

60 kdown rescued reduction in DeltaNp63alpha by FIH-1 depletion.

61 inal transactivation domain (CTAD) of HIF by FIH-1 prevents CTAD association with transcriptional coa

62 lated further by asparagine hydroxylation by FIH (factor-inhibiting HIF), which affects recruitment o

63 (OTUB1) is a substrate for hydroxylation by FIH on N22.

64 about their recognition and hydroxylation by FIH.

65 is a target for functional hydroxylation by FIH.

66 coordinate (6C), whereas (Fe(II)/alphaKG/CAD)FIH is found to be a 5C/6C mixture.

67 with proliferative capacity in a conditional FIH-1 transgenic mouse.

68 nstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis a

69 id not significantly differ between Vil1-Cre/FIH(+f/+f) and wild-type mice.

70 ane/dextran sodium sulfate model in Vil1-Cre/FIH(+f/+f) and wild-type siblings.

71 Vil1-Cre/FIH(+f/+f) mice showed a less severe colitis progress co

72 ociated with the immune response in Vil1-Cre/FIH(+f/+f) mice.

73 An enzyme-dead FIH-1 mutation failed to restore glycogen stores, indica

74 s a transcriptional repressor that decreases FIH-1 expression and subsequently leads to a decrease in

75 A total of 82 publications describing FIH trials were selected for analysis.

76 Elevating FIH-1 levels in primary human epidermal keratinocytes (H

77 expression of its target gene FIH, encoding FIH [factor inhibiting hypoxia-inducing factor 1alpha (H

78 By contrast, endogenous FIH activity was reduced in fibroblasts from patients wi

79 inhibition of miR-31-5p results in enhanced FIH expression and suppression of HIF-1 signaling, while

80 selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against

81 dy, we examined the role of colon epithelial FIH in a mouse model of colitis-induced colorectal cance

82 ppression of HIF-1-TAD activity by exogenous FIH-1.

83 factor inhibiting hypoxia-inducible factor (FIH) enhances both glycolysis and aerobic metabolism.

84 Factor inhibiting hypoxia-inducible factor (FIH) is an alpha-ketoglutarate (alphaKG)-dependent enzym

85 factor inhibiting hypoxia-inducible factor (FIH) is an important regulator of the transcriptional ac

86 factor-inhibiting hypoxia-inducible factor (FIH).

87 factor-inhibiting hypoxia-inducible factor (FIH).

88 t competition between HIF-alpha and ARDs for FIH is likely to be biologically relevant, particularly

89 that forms in solution and is essential for FIH activity.

90 a-independent manner is a novel function for FIH-1 and provides new insight into how the corneal epit

91 lthough the consensus chemical mechanism for FIH proposes that CTAD binding triggers O2 activation by

92 ZG-2305, with a K(i) of 79.6 nM for FIH, manifests 38-fold selectivity over the hypoxia-indu

93 itors, consistent with an important role for FIH in the hypoxic transcriptional response.

94 inetic SIEs observed in the steady state for FIH can be explained by a strong Fe-OH2 bond.

95 iting HIF1alpha (FIH) and is a substrate for FIH-mediated hydroxylation via an oxygen-dependent mecha

96 es of HIF and ARD proteins as substrates for FIH.

97 dentification of LRRK1 as a novel target for FIH-1 provides new insight into how FIH-1 functions as a

98 have identified multiple non-HIF targets for FIH.

99 ports, we found lower Km(app)(O2) values for FIH than for PHD2 with all HIF-derived substrates.

100 ted to a decrease in the level of functional FIH that has been identified in our previous work.

101 s promotes the expression of its target gene FIH, encoding FIH [factor inhibiting hypoxia-inducing fa

102 Factor Inhibiting HIF (FIH) catalyzes the beta-hydroxylation of asparagine resi

103 ctor (HIF)-1alpha and factor inhibiting HIF (FIH) hydroxylase oxygen-sensing pathway and using HIF-1a

104 The factor inhibiting HIF (FIH) is a proximate oxygen sensor for human cells, hydro

105 Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF fu

106 yl hydroxylase termed factor-inhibiting HIF (FIH) negatively regulate HIF.

107 araginyl hydroxylase (factor-inhibiting HIF (FIH)).

108 paragine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducib

109 rt that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF

110 roxylases (PHD1-3 and factor-inhibiting HIF (FIH), respectively).

111 n vitro, knockdown of Factor Inhibiting HIF (FIH), which modulates HIF activity, or oxidative stress

112 HD1-3 or EGLN1-3) and factor inhibiting HIF (FIH).

113 sparagine hydroxylase factor inhibiting HIF (FIH).

114 eracts with the factor inhibiting HIF1alpha (FIH) and is a substrate for FIH-mediated hydroxylation v

115 rget for FIH-1 provides new insight into how FIH-1 functions as a positive regulator of epithelial mi

116 kers of drug activity before first in human (FIH) studies.

117 in experimental data, guide first-in-human (FIH) dose selection, design dosing regimens with expande

118 plementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly d

119 In addition, the first-in-humans (FIH) dose of 485 mg, determined from the MLP-corrected a

120 xia-inducible factor asparaginyl hydroxylase FIH and histone N(epsilon)-methyl lysine demethylases, i

121 or HIF-2alpha by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation.

122 h the asparaginyl and histidinyl hydroxylase FIH-1 (factor inhibiting hypoxia-inducible factor 1 [HIF

123 with other structurally known hydroxylases, FIH-1 is comprised of a beta-strand jellyroll core with

124 tionship, BioID proteomics assays identified FIH-1 binding partners that had the potential to regulat

125 physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treat

126 (Fe(II))FIH and (Fe(II)/alphaKG)FIH are found to be six-coordina

127 uding those of the Notch pathway, changed in FIH-1-silenced cells.

128 homeodomain protein (CDP/Cut) is involved in FIH transcriptional regulation and is controlled by a sp

129 on, the diminished Akt signaling observed in FIH-1-overexpressing HCEKs could be restored by the addi

130 table Fe-OH2 bond plays an important part in FIH's regulatory role over O2 homeostasis in humans and

131 probe of substrate-triggered aquo release in FIH, as inverse SIEs (SIE < 1) are signatures for pre-eq

132 s), and a miR-31-resistant FIH-1 to increase FIH-1 levels.

133 Increased FIH resulted in a switch from glycolysis to oxidative ph

134 se distinct features are likely to influence FIH substrate choice in vivo and, therefore, have import

135 d 2OG derivatives, 10 enhance and 17 inhibit FIH activity.

136 G derivatives selectively enhance or inhibit FIH or AspH.

137 lytic enzymes, and the HIF-1alpha inhibitor (FIH) inhibits HIF-1 activity.

138 re-steady-state conditions, the O2-initiated FIH reaction is significantly faster than that of PHD2.

139 e, as demonstrated by studies with the L340R FIH variant, which is unable to dimerize.

140 e HIF prolyl hydroxylases (PHDs) which, like FIH, are 2-oxoglutarate (2OG) oxygenases.

141 Mechanistically, FIH-defective myeloid cells acquire tumor-supportive pro

142 tion site in CDP (serine 987) that modulates FIH expression.

143 Under normoxia, FIH-1 (factor inhibiting HIF-1) inhibits the transcripti

144 ellular inhibition of PHD2, but probably not FIH, by fumarate and succinate may play a role in the Wa

145 l association with substrates such as Notch, FIH-1 activity does not represent a major mechanism by w

146 of HIF-1alpha indicating that the action of FIH-1 and miR-31 on glycogen is HIF-1alpha-independent.

147 s to a decrease in the repressor activity of FIH-1.

148 Modeling shows that, when Arg238 of FIH is removed, the facial triad carboxylate binds to Fe

149 The limbal epithelial cells of FIH-1 null mice had an increase in glycogen levels as we

150 Comparison of FIH structures complexed with 2OG derivatives to those f

151 nd functional studies on the consequences of FIH-mediated asparaginyl hydroxylation of TRPA1.

152 tural context is an important determinant of FIH-recognition, but analyses of chimeric substrate prot

153 e investigated the molecular determinants of FIH substrate recognition, with a focus on differences b

154 F-alpha by inhibiting the mRNA expression of FIH-1 (factor inhibiting HIF-1) in RCC and thereby promo

155 Although both mRNA and protein expression of FIH-1 decreased in hypoxia, only Mint3 protein levels we

156 ful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy

157 highlights the broad design heterogeneity of FIH trials testing mAbs.

158 rosine, enabling the selective inhibition of FIH over other Jumonji C subfamily 2OG oxygenases.

159 Two known interactors of FIH-1, apoptosis-stimulating of P53 protein 2 (ASPP2) an

160 Combined knockdown of FIH and PHD-selective inhibition did not further increas

161 The knockdown of FIH is associated with increased Notch2 activity, leadin

162 we show that overexpression or knockdown of FIH rescued the effects of miR-31-5p or miR-31-5p inhibi

163 Knockdown of FIH-1 enhances keratinocyte differentiation.

164 Nuclear levels of FIH-1 and Mint3 decreased in hypoxia, and the use of spe

165 Genetic loss of FIH promotes both glycolysis and aerobic metabolism.

166 Conversely, loss of FIH-1 in vivo and in vitro attenuated DeltaNp63alpha exp

167 Loss of FIH-1 in vivo increased Notch activity in the limbal epi

168 Nonetheless, the molecular mechanism of FIH regulation in cancer, in particular RCC, was unclear

169 Point mutants of FIH were prepared to test the functional role of the alp

170 Overexpression of FIH-1 was able to reduce HIF-1 function, as seen by chan

171 F hydroxylases, we compared the reactions of FIH and PHD2 with O2.

172 R-31) is an endogenous negative regulator of FIH-1 expression that results in keratinocyte differenti

173 ing appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals b

174 assays demonstrate that the positive role of FIH-1 in migration is independent of Notch signaling, su

175 e of this study was to determine the role of FIH-1 in regulating HIF-1 activity in the nucleus pulpos

176 ngiogenesis, we here investigate the role of FIH/Notch signaling in endothelial cells.

177 emical results extend the substrate scope of FIH catalysis and may have implications for its biologic

178 s regulation by binding and sequestration of FIH-1 by Mint3.

179 microarray results after stable silencing of FIH-1 showed no significant changes in transcripts of cl

180 the molecular contacts at the active site of FIH-1 have been elucidated and provide a platform for fu

181 X-ray crystal structures of FIH in complex with Fe(II) and fumarate or succinate rev

182 e the geometric and electronic structures of FIH in its (Fe(II)), (Fe(II)/alphaKG), and (Fe(II)/alpha

183 Our mechanistic studies of FIH have revealed inverse solvent isotope effects in the

184 s the Warburg effect via direct targeting of FIH.

185 Treatment of FIH-1-transduced HCEKs with either a myristolated Akt or

186 down of PHD-2, but not knockdown of PHD-1 or FIH-1, dramatically augmented HIF-1alpha expression, mod

187 target gene expression is induced by PHD or FIH inhibition.

188 llular compartmentalization of overexpressed FIH-1 was critical for its regulation of HIF-1 activity

189 increase in pericellular pO(2) than the PHD/FIH-selective HIs.

190 Like the PHDs, FIH is proposed to have a hypoxia-sensing role in cells,

191 Antago-31 raised FIH-1 levels and significantly reduced glycogen stores i

192 rovirally transduced with a miR-31-resistant FIH-1 had markedly reduced glycogen levels compared with

193 eratinocytes (HCEKs), and a miR-31-resistant FIH-1 to increase FIH-1 levels.

194 of a series of novel, potent, and selective FIH inhibitors that occupy both the FIH catalytic site a

195 Under the assay conditions, no significant FIH inhibition was observed by the TCAIs or pyruvate, bu

196 Silencing FIH-1 in HCEKs reversed the observed changes in Akt-sign

197 ASPP2 is reported to undergo a single FIH-catalyzed hydroxylation at Asn-986.

198 5p enhances the Warburg effect via targeting FIH.

199 Our data support the concept that FIH-1 may interact with Notch2 and repress its activity,

200 In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a tran

201 to restore glycogen stores, indicating that FIH-1 negatively regulates glycogen in a hydroxylase-ind

202 We report that FIH-1 silencing in HUVECs results in reduced growth and

203 Collectively, our data reveal that FIH-1 positively regulates DeltaNp63alpha in keratinocyt

204 Here we show that FIH-1 expression is up-regulated in diseased epidermis a

205 We show that FIH-1 null mutant mice exhibit delayed wound healing.

206 l and crystallographic evidence showing that FIH catalyzes the unprecedented post-translational hydro

207 correlate with cellular studies showing that FIH is active at lower O2 concentrations than the PHDs a

208 Functional studies suggest that FIH-mediated hydroxylation may be linked to allyl isothi

209 s still able to bind to FIH, suggesting that FIH may interact in cells with natural ankyrin repeats w

210 elective FIH inhibitors that occupy both the FIH catalytic site and a recently defined tyrosine confo

211 To elucidate the FIH-1/p63 relationship, BioID proteomics assays identifi

212 H in cells, in a manner likely involving the FIH dimer interface, as demonstrated by studies with the

213 gated the kinetics with respect to O2 of the FIH reaction with ankyrin repeat domain (ARD) substrates

214 defined a unique CDP/Cut binding site on the FIH promoter.

215 tation assays, we show that CDP binds to the FIH-1 promoter in vivo and that this binding is PKC zeta

216 Thus, FIH follows the general mechanistic strategy of non-heme

217 Thus, FIH knockout in colon epithelial cells did not modulate

218 Thus, FIH may act as a tumor suppressor in colorectal cancer d

219 our ankyrin repeats is still able to bind to FIH, suggesting that FIH may interact in cells with natu

220 he ARD proteins and reduces their binding to FIH.

221 Limbal and corneal epithelia from wild-type FIH-1(-/-) and Kit(W/Wv) mice were stained with periodic

222 absent in primary hippocampal cultures when FIH activity is lacking.

223 Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation o

224 a less severe colitis progress compared with FIH(+f/+f) animals and a lower number of infiltrating ma

225 droxylase given its structural homology with FIH-1 and JMJD6.

226 it mediates a high affinity interaction with FIH in the presence of cell lysate or macromolecular cro

227 periments indicate that TRPA1 interacts with FIH in cells, in a manner likely involving the FIH dimer

228 helial keratinocytes (HCEKs) transduced with FIH-1 were treated with c-kit ligand to establish furthe