ライフサイエンスコーパス: IRP2

1 set1A, P = 0.029 for aatA, and P = 0.04 for irp2).

2 bolism, including iron regulatory protein 2 (IRP2).

3 tabolism genes by iron regulatory protein 2 (IRP2).

4 the iron regulatory proteins (IRPs) IRP1 and IRP2.

5 on regulatory RNA-binding proteins, IRP1 and IRP2.

6 low-iron diet that is sufficient to activate IRP2.

7 ivated IRP1 and allowed it to substitute for IRP2.

8 raded at a rate similar to that of wild-type IRP2.

9 t this cytosolic protein is neither IRP1 nor IRP2.

10 ivity in Ba/F3-gp55 cells is attributable to IRP2.

11 ed to reduce the abundance of phosphorylated IRP2.

12 but had no effect on IRE binding activity of IRP2.

13 composed of a stable but inactive species of IRP2.

14 RP1 by the E3 ligase FBXL5 that also targets IRP2.

15 -dependent ubiquitination and degradation of IRP2.

16 ons of the iron regulatory proteins IRP1 and IRP2.

17 lation was suppressed by FDXR deficiency via IRP2.

18 cells, in part by iron regulatory protein 2 (IRP2), a protein that is degraded efficiently by the pro

19 Here we show that in Yersinia pestis, irp2, a gene encoding the synthetase (HMWP2) for the sid

20 transcriptional activation by HIF-1, because IRP2 accumulates in Hepa-1 cells lacking a functional HI

21 on availability, accompanied by constitutive IRP2 accumulation and misexpression of IRP2 target genes

22 tween Fe-S cluster assembly, FBXL5, and IRP1/IRP2 activity are poorly defined.

23 IRP1 and IRP2, IFN-gamma treatment decreased IRP2 activity in an NO-independent manner.

24 cytosolic aconitase in mammalian tissues and IRP2 activity increases to compensate for loss of the IR

25 er in which iron levels are sensed to affect IRP2 activity is poorly understood.

26 ession and iron-regulatory protein (IRP1 and IRP2) activity.

27 in a putative siderophore biosynthetic gene (irp2) also decreased expression.

28 P2s lacking a 73 amino acid domain unique to IRP2 and a mutant IRP1 containing an insertion of this d

29 n of IRP2 have employed cells overexpressing IRP2 and also rendered iron deficient to further increas

30 a-induced post-transcriptional regulation of IRP2 and HIF-1alpha.

31 and iron regulatory protein 2 (also known as IRP2 and Ireb2), sense cytosolic iron levels and posttra

32 the solution properties of apo-IRP1 and apo-IRP2 and the interaction with their RNA ligand, the iron

33 reased binding of iron regulatory protein 2 (IRP2) and decreased binding of IRP1 to a consensus iron-

34 creased levels of iron regulatory protein 2 (IRP2) and/or increased IRE-binding activity of IRP1.

35 The neurodegenerative disease of IRP2(-/-) animals progresses slowly as the animals age.

36 In cell lines derived from IRP2(-/-) animals, and in the cerebellum, brainstem, and

37 IRP1 and IRP2 are cytosolic RNA-binding proteins that bind RNA st

38 Our data indicate that IRP1 and IRP2 are differentially regulated by NO. in rat hepatoma

39 NA-binding iron regulatory proteins IRP1 and IRP2 are inactivated by either Fe-S cluster insertion or

40 Although both IRP1 and IRP2 are overexpressed in breast cancer, the overexpress

41 Although IRP1 and IRP2 are similar proteins in that they are ubiquitously

42 Iron regulatory proteins (IRP1 and IRP2) are master regulators of cellular iron metabolism.

43 Iron regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that affect the translati

44 Iron-regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that bind to stem-loop st

45 Iron-regulatory proteins 1 and 2 (IRP1 and IRP2) are RNA-binding proteins that post-transcriptional

46 nrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lun

47 d iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have

48 the degradation of IRP2, with almost all the IRP2 being degraded by a nonproteasomal pathway.

49 In short, when iron is depleted, IRP1 or IRP2 bind IREs; this decreases the synthesis of proteins

50 The two iron regulatory proteins IRP1 and IRP2 bind to transcripts of ferritin, transferrin recept

51 nct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are deplet

52 IRP1 and IRP2 binding activities are regulated by intracellular i

53 IRP2 binding activity may be a novel therapeutic target

54 These results suggest that IRP2 binding activity reduces ferritin expression in the

55 trans-loop base pairs contribute to maximum IRP2 binding and translational regulation.

56 RE to a C-bulge, by deletion of U, decreased IRP2 binding by >95%, whereas IRP1 binding changed only

57 ntribution of the IRE internal loop/bulge to IRP2 binding by comparing natural and engineered IRE var

58 tes (IRP1 + IRP2), confirming differences in IRP2 binding observed for the oligomers.

59 IRP2 binding requires the conserved C-G base pair in the

60 We show 1) equivalent IRP1 and IRP2 binding to multiple TfR-IRE RNAs; 2) increased IRP-

61 Moreover, IRP2 binding to natural IREs with the C-bulge was simila

62 each TfR-IRE folds into an IRE that has low IRP2 binding, whereas a loop/bulge in the stem of the fe

63 the ferritin-IRE allows equivalent IRP1 and IRP2 binding.

64 with ferritin-IRE conformation and enhanced IRP2 binding; and 4) variable IRP1 and IRP2 expression i

65 The increased IRP2-binding activity in zinc-deficient cells coincided

66 During iron deficiency, IRP2 binds IREs to regulate mRNA translation or stabilit

67 There are two known IRPs, IRP1 and IRP2, both of which can respond to iron fluxes in the ce

68 We generated a model of IRP2 bound to RNA and found that two cysteines (C512 and

69 rivation reduces the RNA-binding activity of IRP2 but not IRP2-C512S or IRP2-C516S, consistent with t

70 is restored by simultaneous deletion of the IRP2, but not IRP1, gene.

71 ssed in breast cancer, the overexpression of IRP2, but not IRP1, is associated with decreased ferriti

72 Second, synthesis of IRP2, but not of IRP1, is detectable in Ba/F3-gp55 cells

73 PMA stimulated phosphorylation of IRP1 and IRP2 by at least 2-3-fold without affecting incorporatio

74 Elevating the cellular level of IRP2 by inducing iron deficiency or by transfection caus

75 Iron regulates IRP2 by mediating its rapid proteasomal degradation, whe

76 esis and thiol modification show that, while IRP2 C512 and C516 do not directly interact with RNA, bo

77 th the formation of a disulfide bond between IRP2 C512 and C516 during oxidative stress.

78 ces the RNA-binding activity of IRP2 but not IRP2-C512S or IRP2-C516S, consistent with the formation

79 nding activity of IRP2 but not IRP2-C512S or IRP2-C516S, consistent with the formation of a disulfide

80 ferritin or TfR expression by iron and that IRP2 can act as the sole IRE-dependent mediator of cellu

81 We found that IRP2-/- cells misregulated iron metabolism when cultured

82 D), in virulence gene profiles (fyuA, irp1, irp2, chuA, fepC, ibeA, kpsMII, iss), in having a larger

83 -fold in rabbit reticulocyte lysates (IRP1 + IRP2), confirming differences in IRP2 binding observed f

84 obis(2-nitrobenzoic acid) (DTNB), indicating IRP2 contains a cysteine(s) that is (are) necessary for

85 IREs) and iron-regulatory proteins (IRP1 and IRP2), controlling either mRNA translation or stability.

86 ith iron-regulatory protein-1 (IRP1) whereas IRP2 controls the mRNAs encoding the L- and H-subunits o

87 Iron regulatory protein 2 (IRP2) controls the synthesis of many proteins involved i

88 tion of iron regulatory protein 1 (IRP1) and IRP2 coordinate the use of messenger RNA-encoding protei

89 homeostasis through the redox regulation of IRP2 cysteines.

90 for IRP2, which allowed study of endogenous IRP2 degradation in HEK293A cells under more physiologic

91 iron and oxygen availability and facilitates IRP2 degradation in iron replete cells.

92 We now show evidence suggesting that this IRP2 degradation may be mediated by heme.

93 ulated by a proteolytic pathway that couples IRP2 degradation to intracellular iron levels through th

94 OG) and showed that it blocked iron-mediated IRP2 degradation.

95 pathway to account for the major fraction of IRP2 degradation.

96 Mice that lack IRP2 develop microcytic anemia and neurodegeneration ass

97 These data suggested that IRP2 does not contain a 4Fe-4S cluster similar to the cl

98 Thus, IRP2 dominates post-transcriptional regulation of iron m

99 Thus, IRP2 dominates regulation of mammalian iron homeostasis

100 data show that reversible phosphorylation of IRP2 during G(2)/M has a role in modulating the iron-ind

101 Differential regulation of IRP1 and IRP2 during hypoxia may regulate specific IRP target mRN

102 in activity and expression of both IRP1 and IRP2 during phorbol 12-myristate 13-acetate (PMA)-induce

103 There are two identified IRPs, IRP1 and IRP2, each of which binds consensus IREs present in euka

104 IX and zinc protoporphyrin are generated in IRP2-/- erythroid cells.

105 In contrast, IRP2 exists as monomer in both the apo-IRP2 form and in

106 IRP1 and IRP2 expressed in yeast bind the IRE RNA with high affin

107 anced IRP2 binding; and 4) variable IRP1 and IRP2 expression in human cells and during development (I

108 ith breast cancer demonstrate that increased IRP2 expression is associated with high-grade cancer.

109 Increased IRP2 expression is observed in luminal A, luminal B, and

110 itin ligase complex containing FBXL5 targets IRP2 for proteasomal degradation under iron- and oxygen-

111 complex containing the FBXL5 protein targets IRP2 for proteasomal degradation.

112 rast, IRP2 exists as monomer in both the apo-IRP2 form and in the IRP2/IRE complex.

113 ch after striatal ICH, the effect of IRP1 or IRP2 gene knockout on ferritin expression and injury was

114 strains with mutations in either the psn or irp2 gene were avirulent in mice when inoculated subcuta

115 Most studies on the degradation of IRP2 have employed cells overexpressing IRP2 and also re

116 Two IRPs, IRP1 and IRP2, have been identified previously.

117 IRP2(-/-) hearts contained less ferritin than controls b

118 Further deletion of the irp2 homologue eqbE, or the genes eqbH, eqbI and eqbJ en

119 ment (IRE)-binding activity of both IRP1 and IRP2, IFN-gamma treatment decreased IRP2 activity in an

120 ssess the relative contributions of IRP1 and IRP2 in epithelial cells.

121 icient conditions, the steady-state level of IRP2 in HEK293A cells is regulated by the nonproteasomal

122 lates the RNA binding activities of IRP1 and IRP2 in human 293 and in mouse Hepa-1 cells.

123 re the consequences of loss of both IRP1 and IRP2 in mammalian cells.

124 e the effects of genetic ablation of IRP1 to IRP2 in mice.

125 he role of NO. in the regulation of IRP1 and IRP2 in rat hepatoma cells was investigated by using the

126 expressed wild-type and mutant rat IRP1 and IRP2 in the yeast Saccharomyces cerevisiae.

127 Knockdown of IRP2 in triple-negative MDA-MB-231 human breast cancer c

128 e iron-regulatory proteins 1 and 2 (IRP1 and IRP2) in a rat hepatoma cell line.

129 he degradation of iron regulatory protein 2 (IRP2) in iron-replete cells is a key event in this pathw

130 Irp2 increased mitochondrial iron loading and levels of

131 inyl acetone will inhibit the degradation of IRP2 induced by iron but not that induced by heme.

132 Moreover, iron-dependent oxidation converts IRP2 into a substrate for ubiquitination in vitro.

133 monomer in both the apo-IRP2 form and in the IRP2/IRE complex.

134 h a targeted disruption of the gene encoding Irp2 (Ireb2).

135 that the region of IRP2 that is involved in IRP2 iron-mediated degradation lies outside of the 73-am

136 Several laboratories have shown that IRP2 is also degraded in cells treated with iron salts.

137 These results suggest that dysregulation of IRP2 is an early nodal point underlying altered iron met

138 r stability, whereas during iron sufficiency IRP2 is degraded by the proteasome.

139 used previously to study IRP1, we find that IRP2 is degraded in rabbit fibroblast cells exposed to h

140 Because simultaneous knockout of IRP1 and IRP2 is embryonically lethal, it has not been possible t

141 Hypoxic activation of IRP2 is not because of an increase in transcriptional ac

142 Here, we demonstrate that IRP2 is oxidized and ubiquitinated in cells before degra

143 to basal mammalian iron homeostasis, whereas IRP2 is sensitive to iron status and can compensate for

144 e site-specific oxidations in IRP2, oxidized IRP2 is ubiquitinated, and ubiquitinated IRP2 subsequent

145 Iron regulatory protein 2 (IRP2) is a central regulator of cellular iron homeostasi

146 Iron regulatory protein 2 (IRP2) is a key iron sensor that post-transcriptionally r

147 Iron regulatory protein 2 (IRP2) is an RNA-binding protein that regulates the postt

148 IRP1 and IRP2 isolated from PMA-treated cells displayed different

149 nvolved in iron metabolism, and the level of IRP2 itself is regulated by varying the rate of its degr

150 Further, IRP2 knockdown reduces growth of MDA-MB-231 cells in the

151 out, but was reduced by approximately 60% by IRP2 knockout.

152 t 3 days, and was significantly increased in IRP2 knockouts but not in IRP1 knockouts.

153 Corresponding levels in IRP2 knockouts were increased by 11-fold and 8.4-fold, r

154 In contrast, IRP2 lacks detectable aconitase activity and functions e

155 IRP2 protein levels; however, cobalt-induced IRP2 lacks RNA binding activity.

156 e that the disruption of mouse IRP1, but not IRP2, leads to profound HIF2alpha-dependent abnormalitie

157 er, our data indicate that hypoxia increases IRP2 levels by a post-translational mechanism involving

158 rotein 1 (IRP1) was activated, and increased IRP2 levels, indicative of relative cytosolic iron deple

159 rendered iron deficient to further increase IRP2 levels.

160 or 1 (TfR1) expression, whereas knockdown of IRP2 marginally affected IRE binding activity but caused

161 rted in iron regulatory protein 2-deficient (IRP2 -/-) mice coinciding with increased ferritin levels

162 In this study, we fed IRP2(-/-) mice a diet supplemented with a stable nitroxi

163 We suggest that Tempol protected IRP2(-/-) mice by disassembling the cytosolic iron-sulfu

164 ounced increase in non-heme iron was seen in IRP2-/- mice between 6 and 12 weeks of age, stemming fro

165 TfR expression in erythroid precursors of IRP2-/- mice is reduced, and bone marrow iron stores are

166 f IRP1 greatly exceeds that of IRP2, whereas IRP2-/- mice misregulate the expression of target protei

167 tem, evidence of abnormal iron metabolism in IRP2-/- mice precedes the development of adult-onset pro

168 IRP2-/- mice represent a new paradigm of genetic microcy

169 egulate expression of the same target genes, IRP2-/- mice significantly misregulate iron metabolism a

170 C-bulge iso-IREs bind IRP2 more poorly, as oligomers (n = 28-30), and have a w

171 Third, the Ba/F3 family of cells express IRP2 mRNA at a level similar to other murine cell lines,

172 subunit, nor is it because of an increase in IRP2 mRNA stability.

173 ssion in human cells and during development (IRP2-mRNA predominated).

174 We postulate that IRP2 mutations or deletions may be a cause of refractory

175 synthesis of Psn and proteins encoded by the irp2 operon as well as decreased expression from the psn

176 ell lines were created in which either IRP1, IRP2, or both were knocked down.

177 Mutations in the irp1, irp2, or ybtE gene yielded strains defective in sideroph

178 5 plays a critical role in limiting IRP1 and IRP2 overaccumulation when cytosolic Fe-S cluster assemb

179 Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR

180 lity to catalyze site-specific oxidations in IRP2, oxidized IRP2 is ubiquitinated, and ubiquitinated

181 esence of aap (P = 0.004), astA (P = 0.001), irp2 (P = 0.0006), pet (P = 0.002), and set1A (P = 0.014

182 EAEC virulence genes aap, aatA, aggR, astA, irp2, pet, set1A, and shf was determined by PCR.

183 Here, we identify an iron-independent IRP2 phosphorylation site that is regulated by the cell

184 demonstrate that iron regulatory protein 2 (IRP2) plays a key role in iron accumulation in breast ca

185 COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals wi

186 Here we show that a mutant IRP2 protein lacking this 73-amino acid region degraded

187 sion and a concomitant reduction in IRP1 and IRP2 protein level and RNA-binding activity.

188 RNA binding activity results from increased IRP2 protein levels.

189 a-inducible factor 1 (HIF-1), also increases IRP2 protein levels; however, cobalt-induced IRP2 lacks

190 nvolved in the oxygen and iron regulation of IRP2 protein stability.

191 The accumulation of IRP2 protein was independent of zinc deficiency-induced

192 t cells coincided with an increased level of IRP2 protein.

193 degradation of both the wild-type and mutant IRP2 proteins.

194 ariations in IRE structure and cellular IRP1/IRP2 ratios can provide a range of finely tuned, mRNA-sp

195 overexpression of iron regulatory protein 2 (IRP2) recapitulates many aspects of the alterations in f

196 on sensing via the FBXL5 hemerythrin domain, IRP2 regulation, and cellular responses to maintain mamm

197 teine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA tran

198 ies showed that iron-mediated degradation of IRP2 requires the presence of critical cysteines that re

199 a iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively).

200 Here, we report that ablation of IRP2 results in iron-limited erythropoiesis.

201 Sequence analysis of the region upstream of irp2 revealed the presence of a gene (ybtA) with homolog

202 Site-directed mutagenesis of IRP1 and IRP2 reveals that, although the binding affinities for c

203 The hypoxic increase in IRP2 RNA binding activity results from increased IRP2 pr

204 IRP1 RNA binding activity, hypoxia increases IRP2 RNA binding activity.

205 eductant to cobalt-treated extracts restored IRP2 RNA binding activity.

206 degradation, but studies have suggested that IRP2 RNA binding is also regulated by thiol oxidation.

207 Decreased IRP2 RNA binding is correlated with reduced transferrin

208 er-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthes

209 phosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthes

210 t synthesis increase, and a late phase where IRP2 RNA-binding activity increases and iron uptake and

211 During the late phase of hypoxia, IRP2 RNA-binding activity increases, becoming the domina

212 IRP2 RNA-binding activity is primarily regulated by iron

213 ein increases concomitant with a decrease in IRP2 RNA-binding activity.

214 rovide insight into the structural basis for IRP2-RNA interactions and reveal an iron-independent mec

215 ing cleft and must be unmodified/reduced for IRP2-RNA interactions.

216 experiments demonstrated that IRP1, but not IRP2, selectively bound the APP IRE in human neural cell

217 IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during

218 rotein levels were dramatically decreased in Irp2(-/-) spleens, whereas ferrochelatase mRNA levels we

219 ctivity may be involved in the regulation of IRP2 stability.

220 zed IRP2 is ubiquitinated, and ubiquitinated IRP2 subsequently is degraded by the proteasome.

221 utive IRP2 accumulation and misexpression of IRP2 target genes.

222 These data indicate that the region of IRP2 that is involved in IRP2 iron-mediated degradation

223 geted deletion of iron regulatory protein 2 (IRP2-/-) that have been reported to develop neurodegener

224 The responsiveness of IRP2 to low iron is specifically enhanced in the duodena

225 s, iron regulatory protein 1 and 2 (IRP1 and IRP2) to stem loop structures, known as iron-responsive

226 We show that the heme-oxidized IRP2 ubiquitin ligase 1 interacting protein (HOIP) compo

227 The levels of expression of heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), HOIL-1-interacting p

228 interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1-interacting

229 ly interact with LUBAC subunit Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1L) and conjugate K48-link

230 In addition, hypoxia, DFO and DMOG blocked IRP2 ubiquitination.

231 In contrast to IRP1, IRP2 was highly phosphorylated in untreated cells.

232 Like IRP1, the RNA-binding activity of IRP2 was sensitive to inactivation by N-ethylmaleimide (

233 inding activity, the RNA-binding activity of IRP2 was unaffected using the same iron treatment.

234 the biochemical characteristics of IRP1 and IRP2, we expressed wild-type and mutant rat IRP1 and IRP

235 s of multiple IRE interactions with IRP1 and IRP2 were compared between the native TfR-3'-UTR sequenc

236 Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced ex

237 promoter/operators designated tox, IRP1, and IRP2 were reported previously.

238 ession level of IRP1 greatly exceeds that of IRP2, whereas IRP2-/- mice misregulate the expression of

239 expression of the iron regulatory protein-2 (IRP2), which increases the intracellular iron pool.

240 utilized a sensitive, quantitative assay for IRP2, which allowed study of endogenous IRP2 degradation

241 ed by the iron regulatory proteins, IRP1 and IRP2, which regulate proteins involved in iron homeostas

242 h the virulence genes aggR, set1A, aatA, and irp2, which were found in 16 (40%), 17 (43%), 10 (25%),

243 on of the iron regulatory proteins (IRP1 and IRP2) with canonical IREs controls iron-dependent transl

244 lays only a minor role in the degradation of IRP2, with almost all the IRP2 being degraded by a nonpr

245 cation of the irp1 gene and the positions of irp2, ybtT, and ybtE within the ybt operon.