ライフサイエンスコーパス: ERRalpha

1 ERRalpha activated PPARalpha gene expression via direct

2 ERRalpha deficiency reduced activated T-cell numbers in

3 ERRalpha fulfills this role by acting directly at genes

4 ERRalpha has also been shown to mediate bone-derived mac

5 ERRalpha levels also correlated with expression of ErbB2

6 ERRalpha mRNA was expressed at levels greater than or si

7 ERRalpha regulated macrophage inflammatory responses by

8 ERRalpha regulates reactive oxygen species production, a

9 ERRalpha showed potential as a biomarker of unfavorable

10 ERRalpha upregulated a subset of PGC-1alpha target genes

11 ERRalpha was implicated previously in regulating the gen

12 ERRalpha was recently shown to be a negative prognostic

13 ERRalpha-deficient (Esrra(-/-)) mice showed increased su

14 including estrogen-related receptor alpha-1 (ERRalpha-1), can activate gene transcription in a consti

15 abolism known to be regulated by PGC-1alpha, ERRalpha, and a second nuclear receptor, PPARalpha.

16 Thus, the PGC-1alpha.ERRalpha interaction is distinct from that of other nucl

17 eceptors, is not required for the PGC-1alpha.ERRalpha interaction.

18 ha is completely dependent on the PGC-1alpha/ERRalpha complex and is further modulated by the action

19 s identify the PDK4 gene as a new PGC-1alpha/ERRalpha target and suggest a mechanism whereby PGC-1alp

20 that interferes effectively with PGC-1alpha/ERRalpha-dependent signaling.

21 beta-adrenergic stimulation of a PGC-1alpha/ERRalpha/VEGF axis mediates exercise-induced angiogenesi

22 l and genetic experiments that show that (a) ERRalpha, beta-catenin (beta-cat), and lymphoid enhancer

23 n addition, PGC-1alpha was shown to activate ERRalpha expression.

24 PGC-1alpha was also shown to activate ERRalpha gene expression.

25 drial processes were suppressed in activated ERRalpha(-/-) T cells and T cells treated with two chemi

26 pha, the expression of constitutively active ERRalpha (CA-ERRalpha) was sufficient to enhance metabol

27 Acute ERRalpha inhibition also blocked T-cell growth and proli

28 d Treg--but not Teff--generation after acute ERRalpha inhibition.

29 Estrogen-related receptors (ERR), ERR alpha (ERRalpha) and ERR gamma (ERRgamma), are orphan nuclear r

30 r receptors estrogen-related receptor alpha (ERRalpha) and ERRgamma are essential transcriptional coo

31 C1beta) and estrogen-related receptor alpha (ERRalpha) are aberrantly expressed in human colon cell l

32 whereas the estrogen-related receptor alpha (ERRalpha) bound NRRE-1 in extracts prepared from differe

33 ar receptor estrogen-related receptor alpha (ERRalpha) directs the transcription of nuclear genes inv

34 ar receptor estrogen-related receptor alpha (ERRalpha) has been associated with a negative outcome in

35 The estrogen-related receptor alpha (ERRalpha) has been implicated in endocrine-related cance

36 pression of estrogen-related receptor alpha (ERRalpha) has recently been shown to carry negative prog

37 tivator of oestrogen-related receptor alpha (ERRalpha) in brown adipose tissue.

38 logy of the estrogen-related receptor alpha (ERRalpha) in cultured liver cells.

39 Estrogen-related receptor alpha (ERRalpha) is a key regulator of mitochondrial function a

40 The estrogen-related receptor alpha (ERRalpha) is a potential target for activation in the tr

41 The estrogen-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor su

42 Estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor that has been fu

43 The estrogen-related receptor alpha (ERRalpha) is an orphan receptor belonging to the nuclear

44 r receptor, estrogen related receptor alpha (ERRalpha) is required to coordinate the PGC-1alpha -indu

45 es estrogen receptor-related receptor alpha (ERRalpha) to regulate osteoclastogenesis.

46 ar receptor estrogen-related receptor alpha (ERRalpha) was identified in a yeast two-hybrid screen of

47 Estrogen-related receptor alpha (ERRalpha) was the first orphan nuclear receptor to be id

48 Estrogen-related receptor alpha (ERRalpha), a member of the nuclear receptor superfamily,

49 of estrogen receptor-related receptor alpha (ERRalpha), a nuclear receptor that cooperates with the t

50 t bound the estrogen-related receptor alpha (ERRalpha), a recently identified component of the PGC-1a

51 servations, estrogen-related receptor alpha (ERRalpha), an orphan nuclear receptor known for its role

52 cluding the estrogen-related receptor alpha (ERRalpha), an orphan nuclear receptor.

53 ar receptor estrogen-related receptor alpha (ERRalpha), implicating ERRalpha as a potential mediator

54 1alpha) and estrogen-related receptor alpha (ERRalpha).

55 nd estrogen receptor-related receptor alpha (ERRalpha); and the expression of key oxidative mitochond

56 ar receptor estrogen-related receptor alpha (ERRalpha; NR3B1) is a key metabolic regulator, but its f

57 an receptor estrogen-related receptor-alpha (ERRalpha) for ERalpha.

58 ar receptor estrogen-related receptor-alpha (ERRalpha) regulates metabolic pathways critical for Teff

59 The estrogen-related receptor-alpha (ERRalpha) regulates mitochondrial biogenesis and glucose

60 led by the estrogen-related receptor alpha1 (ERRalpha) mitochondrial master regulator.

61 lated transcriptional regulator, Bcl3, as an ERRalpha coactivator.

62 e demonstrate that monoamine oxidase B is an ERRalpha target gene whose expression is regulated by PG

63 demonstration of functional activities of an ERRalpha ligand in metabolic animal models.

64 a, PGC-1alpha, and Bcl3 form a complex on an ERRalpha-responsive element within the pyruvate dehydrog

65 To examine this hypothesis, we analyzed ERRalpha and ERalpha in recurrent tamoxifen-resistant br

66 se expression is regulated by PGC-1alpha and ERRalpha and inhibited by the ERRalpha inverse agonist.

67 itation assays confirmed that PGC-1alpha and ERRalpha occupied the mPDK4 promoter in C(2)C(12) myotub

68 ated that Bc13 interacts with PGC-1alpha and ERRalpha, allowing for interaction with both proteins.

69 riptional mechanism involving PGC-1alpha and ERRalpha, and thus may be useful in treating age-associa

70 RF1, NRF2, Tfam, COX-II, PPARdelta, CREB and ERRalpha mRNA and mitochondrial DNA (mtDNA), were signif

71 gether, our results suggest that ERalpha and ERRalpha cooperate to promote endocrine resistance, and

72 umber of genes regulated by both ERalpha and ERRalpha led us to expand our study to the more aggressi

73 Beyond differences in the ERalpha and ERRalpha target gene repertoires, both factors were enga

74 etween estrogen receptor alpha (ERalpha) and ERRalpha initially suggested that these receptors may ha

75 eal KSR1-dependent control of PGC1alpha- and ERRalpha-dependent pathways that are necessary and suffi

76 In contrast, PGC1beta and ERRalpha are not detectable in nontransformed human colo

77 rmore, in fibroblasts null for PPARalpha and ERRalpha, the ability of ERRalpha to activate several PP

78 ates reactive oxygen species production, and ERRalpha knockdown attenuates proliferation and colony-f

79 ensitivity to hormonal blockade therapy, and ERRalpha status may also be predictive of ErbB2-based th

80 ssociated with transcription factors such as ERRalpha, NRF-1, and HNF4alpha, however acetylation and

81 form macromolecular complexes in cells, (b) ERRalpha transcriptional activity is enhanced by beta-ca

82 Mice lacking both ERRalpha and cardiac ERRgamma develop severe bradycardia

83 the endocrine signaling pathways mediated by ERRalpha including association with human disease states

84 PDK4 gene, inhibits the induction of PDK4 by ERRalpha and ERRgamma.

85 esponse element or the MCAD gene promoter by ERRalpha and the related isoform ERRgamma.

86 med in vivo occupancy of the OPN promoter by ERRalpha in HT29 cells, suggesting that OPN is a direct

87 Many of the genes regulated by ERRalpha are known targets for the nuclear receptor PPAR

88 ng genes previously shown to be regulated by ERRalpha or beta-cat.

89 ing transcriptional upregulation of WNT11 by ERRalpha and beta-cat that influences the migratory capa

90 ession of constitutively active ERRalpha (CA-ERRalpha) was sufficient to enhance metabolic capacity b

91 n to synergize with PGC-1alpha to coactivate ERRalpha.

92 Consequently, ERRalpha may potentiate constitutive transcription of es

93 A crucial role for controlling ERRalpha-mediated target gene expression has been ascrib

94 Together, our data document ERRalpha and its mitochondrial program as downstream eff

95 In addition, knocking down endogenous ERRalpha led to reduced OPN expression in HT29 colon can

96 n in the target genes controlled by ERalpha, ERRalpha, and their coactivator AIB1, defining a novel s

97 ght to gain a genome-wide picture of ERalpha-ERRalpha cross-talk using an unbiased microarray approac

98 growth factor receptor, ErbB2, ErbB3, ErbB4, ERRalpha, ERRbeta, and ERRgamma were determined in unsel

99 observed in the nonhepatoma cells expressing ERRalpha and ERRgamma.

100 ctional analyses confirmed a requirement for ERRalpha in tamoxifen- and fulvestrant-resistant MCF-7 c

101 unravel a previously unappreciated role for ERRalpha as a negative regulator of TLR-induced inflamma

102 Our results confirm a role for ERRalpha in breast cancer growth and highlight it as a p

103 ithelial cells displayed higher staining for ERRalpha than normal mucosa, in correlation with elevate

104 Further, ERRalpha was required for the regulation of NF-kappaB si

105 On the one hand, ERRalpha and ERRgamma together are vital for intact card

106 On the other hand, ERRalpha and ERRgamma influence major cardiomyocyte ener

107 Hence, ERRalpha and ERRgamma status may be predictive of sensit

108 RRgamma in breast cancer progression and how ERRalpha and ERRgamma may differentially affect cancer g

109 We show that the major isoform of the human ERRalpha gene, ERRalpha1, can sequence-specifically bind

110 These results identify ERRalpha and ERRgamma as novel PGC-1alpha interacting pr

111 ene-expression analysis was used to identify ERRalpha small-molecule regulators and target genes.

112 To identify ERRalpha-regulated pathways in tissues with high energy

113 class of ERRalpha target genes and implicate ERRalpha and chicken ovalbumin upstream promoter transcr

114 lated receptor alpha (ERRalpha), implicating ERRalpha as a potential mediator of PGC-1alpha action.

115 These results indicate that Phe-329 in ERRalpha-1 and Ala-350 in ERalpha play important roles i

116 AM251 induced SUMO-2,3 incorporation in ERRalpha in conjunction with increased protein kinase C

117 Increased ERRalpha levels associated with ER-negative (Fisher's ex

118 In addition, increased ERRalpha expression was linked to reduced overall surviv

119 ells treated with two chemically independent ERRalpha inhibitors or by shRNAi.

120 AMPK activation induced ERRalpha transcript expression in M-ERRalphaWT muscle an

121 rtant regulatory region for estrogen-induced ERRalpha gene expression.

122 tation assays, that 17beta-estradiol induces ERRalpha gene expression in MCF-7 cells through active r

123 satory proliferation observed in DEN-injured ERRalpha-null livers is concomitant with increased nucle

124 In this study, we investigated ERRalpha gene expression and chromatin structural change

125 n NRRE-1, each of which conform to the known ERRalpha monomeric binding consensus.

126 tion of VEGF by PGC-1alpha, and mice lacking ERRalpha also failed to increase vascular density after

127 Here, we show that mice lacking ERRalpha are unable to maintain body temperature when ex

128 M-ERRalpha(-/-) mice exhibited impaired regeneration chara

129 lphaWT) and muscle-specific ERRalpha(-/-) (M-ERRalpha(-/-)) mice after injury by intramuscular cardio

130 ivated protein kinase (AMPK) activation in M-ERRalpha(-/-) muscle.

131 tor (PGC)-1beta, were downregulated in the M-ERRalpha(-/-) muscles at the onset of myogenesis.

132 Adenoviral-mediated ERRalpha overexpression in primary neonatal cardiac myco

133 Moreover, ERRalpha and ERRgamma are candidate targets for therapeu

134 tudy yielded the surprising result that most ERRalpha-regulated genes are unrelated to estrogen signa

135 Our findings highlight a MYC/ERRalpha pathway that contributes to physiological and p

136 athological bone loss by integrating the MYC/ERRalpha axis to drive metabolic reprogramming during os

137 e results of this study suggest that the MYC/ERRalpha pathway should be further explored as a drug ta

138 to a reduced extent in the absence of normal ERRalpha activity.

139 level of expression of many known and novel ERRalpha target genes.

140 In addition to generating a host of novel ERRalpha target genes, this study yielded the surprising

141 diated by proteasomal degradation of nuclear ERRalpha.

142 l for PPARalpha and ERRalpha, the ability of ERRalpha to activate several PPARalpha targets and to in

143 y mediator of the promigratory activities of ERRalpha/beta-cat.

144 gonist inhibits the constitutive activity of ERRalpha in both biochemical and cell-based assays.

145 responsible for the constitutive activity of ERRalpha-1.

146 so inhibited the transcriptional activity of ERRalpha.

147 irst potent and selective inverse agonist of ERRalpha.

148 To date, no small-molecule agonists of ERRalpha have been identified despite several high-throu

149 Ralpha gene expression via direct binding of ERRalpha to the PPARalpha gene promoter.

150 These results identify a new class of ERRalpha target genes and implicate ERRalpha and chicken

151 HDAC3 coactivation of ERRalpha is mediated by deacetylation of PGC-1alpha and

152 The contribution of ERRalpha in breast cancer progression remains unknown bu

153 not prevent AM251-induced destabilization of ERRalpha protein, whereas proteasome inhibition with MG1

154 ugh direct binding to and destabilization of ERRalpha protein.

155 ndrial physiology through destabilization of ERRalpha.

156 al structure of the ligand-binding domain of ERRalpha with lead compound 29 revealed the presence of

157 owever, metabolic target genes downstream of ERRalpha have not been well defined.

158 eptors could override the positive effect of ERRalpha-1.

159 y provide a rationale for the exploration of ERRalpha as a candidate drug target to treat endocrine-r

160 I3K/AKT activity regulates the expression of ERRalpha and mitochondrial biogenesis/respiration.

161 Expression of ERRalpha and of its nucleus-encoded mitochondrial target

162 The expression of ERRalpha paralleled NRRE-1 binding activities and MCAD e

163 pecimens (n = 1041), increased expression of ERRalpha was associated with enhanced proliferation and

164 PGC-1alpha also increased the expression of ERRalpha, PPARalpha, and enzymes that support mitochondr

165 negative correlation between expressions of ERRalpha and PTEN in patients with liver cancer.

166 kinase 2), were reduced when the function of ERRalpha was inhibited in infected cells.

167 ined its DNA-binding function, indicative of ERRalpha being a target of nuclear proteasomal complexes

168 Promoter analysis, inhibition of ERRalpha activity, and expression and mutation of potent

169 oss of MYC and pharmacological inhibition of ERRalpha attenuated bone loss in a mouse model of osteop

170 Accordingly, pharmacological inhibition of ERRalpha attenuated OVX-induced bone loss in mice.

171 Furthermore, in vivo inhibition of ERRalpha reduced T-cell proliferation and Teff generatio

172 CF-7 cells, with pharmacologic inhibition of ERRalpha sufficient to partly restore sensitivity to ant

173 ERRalpha, and treatment with an inhibitor of ERRalpha impeded anchorage-independent growth.

174 Although stable knockdown of ERRalpha expression in MDA-MB-231 cells had no effect on

175 nregulation of PLA2R1 decreases the level of ERRalpha and of its nucleus-encoded mitochondrial target

176 xically, in clinical studies, high levels of ERRalpha are associated with poor outcomes whereas high

177 sting CD4(+) T cells expressed low levels of ERRalpha protein that increased on activation.

178 Herein we show that global loss of ERRalpha accelerates the development of diethylnitrosami

179 Our work thus shows that global loss of ERRalpha activity promotes hepatocellular carcinoma by i

180 d metabolomics studies revealed that loss of ERRalpha promotes hepatocyte necrosis over apoptosis in

181 In particular, we demonstrate that loss of ERRalpha-dependent regulation of the NF-kappaB inhibitor

182 mplying that pharmacological manipulation of ERRalpha activity may have a significant clinical impact

183 myotubes, and cardiac and skeletal muscle of ERRalpha-/- mice.

184 The cardiac perinatal expression pattern of ERRalpha paralleled that of PGC-1alpha and MCAD.

185 Down-regulation of ERRalpha by AM251 or small interfering RNA led to increa

186 et of AKT, plays a role in the regulation of ERRalpha, independent of PKA signaling.

187 The physiological role of ERRalpha has yet to be established primarily because of

188 However, the role of ERRalpha in cancer in which inflammation acts as a tumor

189 To understand the role of ERRalpha in PGC-1alpha signaling, a parallel approach of

190 Furthermore, silencing of ERRalpha and beta-cat expression individually or togethe

191 s, suggesting that OPN is a direct target of ERRalpha in colorectal cancer.

192 Upregulation of ERRalpha or ERRgamma is required for the OXPHOS burst in

193 AM251 analogs also have negative impacts on ERRalpha protein levels in a cell-type-dependent manner

194 ary neonatal cardiac myocytes overexpressing ERRalpha.

195 ty, and expression and mutation of potential ERRalpha response elements in the proximal promoter of h

196 se activation by phorbol ester also promoted ERRalpha protein loss.

197 Rather, ERRalpha binds PGC-1alpha primarily through a Leu-rich m

198 Rather, ERRalpha broadly affected metabolic gene expression and

199 co-activator-1beta) and the nuclear receptor ERRalpha (estrogen receptor-related receptor alpha), and

200 The orphan nuclear receptor ERRalpha mediated the induction of VEGF by PGC-1alpha, a

201 40 was found to require the nuclear receptor ERRalpha to regulate hexose uptake and mitochondrial pro

202 that the estrogen-related nuclear receptors (ERRalpha and ERRgamma) and their partnered co-factors PG

203 PDK4 gene by the estrogen-related receptors (ERRalpha and ERRgamma).

204 ve found that four orphan/nuclear receptors, ERRalpha-1, EAR-2, COUP-TFI (EAR-3), and RARgamma, bind

205 , ectopic PGC1alpha was sufficient to rescue ERRalpha expression, metabolic capacity, and anchorage-i

206 Consistent with the gene expression results, ERRalpha increased myocyte lipid accumulation and fatty

207 the identification of a potent and selective ERRalpha inverse agonist that interferes effectively wit

208 The discovery of potent and selective ERRalpha modulators and their effect on PGC-1alpha signa

209 S1 may function as a positive element since ERRalpha-1 is expressed, but EAR-2 and RARgamma are only

210 wild-type (M-ERRalphaWT) and muscle-specific ERRalpha(-/-) (M-ERRalpha(-/-)) mice after injury by int

211 urther supporting the relevance of targeting ERRalpha with antagonists as anticancer agents.

212 We conclude that ERRalpha is needed for the efficient production of cytom

213 We conclude that ERRalpha serves as a critical nodal point in the regulat

214 Our findings demonstrate that ERRalpha is a key regulator of mitochondrial biogenesis

215 Here, we demonstrate that ERRalpha negatively regulates Toll-like receptor (TLR)-i

216 vitro binding experiments demonstrated that ERRalpha interacts with PGC-1alpha via its activation fu

217 a-null primary fibroblasts demonstrated that ERRalpha is required for PGC-1alpha-mediated activation

218 mmunoprecipitation studies demonstrated that ERRalpha, PGC-1alpha, and Bcl3 form a complex on an ERRa

219 In contrast to the findings that ERRalpha-1 behaves as a positive regulatory factor, thes

220 In this setting, we found that ERRalpha expression is required for the basal level of e

221 eries of NRRE-1 mutant probes indicated that ERRalpha was capable of binding two distinct sites withi

222 ction of the Esrra promoter, indicating that ERRalpha may control gene regulation downstream of the A

223 Here we report that ERRalpha and ERRgamma stimulate the PDK4 gene in hepatom

224 Previous reports that ERRalpha regulates OPN expression in bone prompted us to

225 NativePAGE analysis revealed that ERRalpha formed a approximately 220-kDa multiprotein nuc

226 Rather, we show that ERRalpha is needed for the high levels of mitochondrial

227 e proximal promoter of human OPN showed that ERRalpha and its obligate co-activator, peroxisome proli

228 Collectively, these results suggest that ERRalpha deficiency during muscle regeneration impairs r

229 The results suggest that ERRalpha may be intractable as a direct target for pharm

230 Recent studies suggest that ERRalpha may indeed promote breast tumor growth.

231 The ERRalpha gene is estrogen-responsive in several mouse ti

232 The ERRalpha-1 mutant F329A lost the transactivation activit

233 Finally, blocking the ERRalpha-controlled mitochondrial program largely inhibi

234 PGC-1alpha and ERRalpha and inhibited by the ERRalpha inverse agonist.

235 In contrast, ectopic expression of the ERRalpha coactivator PGC-1alpha enhanced oxidative metab

236 We mapped the nucleosome positions of the ERRalpha promoter around the MHRE region and found that

237 l transfection experiments revealed that the ERRalpha-1 mutant F329A, like wild-type ERalpha, recogni

238 creased migration could be attributed to the ERRalpha/beta-cat-dependent induction of WNT11.

239 unction by promoting NO* bioactivity through ERRalpha induced expression of eNOS.

240 Thus, ERRalpha is a selective transcriptional regulator of Tef

241 Thus, ERRalpha was the most abundant nuclear receptor in a sub

242 ction of a small interfering RNA directed to ERRalpha into the highly aggressive breast carcinoma MDA

243 alpha with PGC-1alpha in a manner similar to ERRalpha.

244 On the other hand, like wild-type ERRalpha-1, the ERalpha mutant A350F was found to be con

245 ously shown to be an antagonist of wild-type ERRalpha-1.

246 Unlike ERRalpha, ERRgamma showed potential as a biomarker of fa

247 Additionally, transfection studies using ERRalpha-null primary fibroblasts demonstrated that ERRa

248 These findings validate ERRalpha as a promising therapeutic target in the treatm

249 activators and release of co-repressors when ERRalpha and AP1 bind and ERalpha is tethered to the MHR

250 replication observed in HepG2 cells, whereas ERRalpha and ERRgamma are probably responsible for the m

251 However, whether ERRalpha controls metabolic remodeling during skeletal m

252 n in bone prompted us to investigate whether ERRalpha controls OPN expression in human colorectal can

253 ngs suggest an additional mechanism by which ERRalpha participates in the development and progression

254 isturbed the interactions of PGC-1alpha with ERRalpha and PPARalpha, factors important for mitochondr

255 independent growth required interaction with ERRalpha, and treatment with an inhibitor of ERRalpha im