ライフサイエンスコーパス: FIH

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

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

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

4 FIH is an asparaginyl hydroxylase catalyzing post-transl

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

29 Although FIH tolerates a variety of chemically disparate residues

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

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

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

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

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

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

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

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

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

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

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

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

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

43 2OG TCAIs as inhibitors of purified PHD2 and FIH.

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

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

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

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

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

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

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

51 is a target for functional hydroxylation by FIH.

52 about their recognition and hydroxylation by FIH.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

71 have identified multiple non-HIF targets for FIH.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

113 Knockdown of FIH-1 enhances keratinocyte differentiation.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

154 he ARD proteins and reduces their binding to FIH.

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

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

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

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

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