ライフサイエンスコーパス: TRbeta

1 TRbeta knock-out (KO) mice have significantly higher TH

2 TRbeta signaling through PI3K provides a molecular expla

3 TRbeta(PV/PV) mice deficient in SRC-3 (TRbeta(PV/PV)SRC-

4 TRbeta(PV/PV) mice lost the negative feedback regulation

5 prehensive expression analysis of TRalpha 1, TRbeta 1, TRbeta 2 (TH binding), and TRalpha 2 (non-TH b

6 expression analysis of TRalpha 1, TRbeta 1, TRbeta 2 (TH binding), and TRalpha 2 (non-TH binding) in

7 the ratios TRalpha 1:TRalpha 2, and TRbeta 1:TRbeta 2.

8 compared with TRbeta(PV/PV) mice with SRC-3 (TRbeta(PV/PV)SRC-3(+/+) mice).

9 TRbeta(PV/PV) mice deficient in SRC-3 (TRbeta(PV/PV)SRC-3(-/-) mice) had significantly increase

10 d skeletal muscle phenotype and function; 3) TRbeta in maintaining a basal level of cellular response

11 A TRbeta mutant defective in DNA binding had only a slight

12 scribed TRbeta message and in vivo against a TRbeta-luciferase fusion protein.

13 hese findings show for the first time that a TRbeta mutation promotes the development of mammary hype

14 GC-1, however, binds to and activates TRbeta at least an order of magnitude better than it doe

15 PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated

16 Our data show that only high affinity TRbeta TRE is occupied by limiting levels of TR during p

17 ences in the ratios TRalpha 1:TRalpha 2, and TRbeta 1:TRbeta 2.

18 a was sumoylated at lysines 283 and 389, and TRbeta at lysines 50, 146, and 443.

19 ided new insights, showing that activity and TRbeta isoform selectivity is highly correlated with the

20 in TRbeta(PV/PV)/Akt1(+/+) (PVPV-Akt1WT) and TRbeta(PV/PV)/Akt1(-/-) (PVPV-Akt1KO) mice.

21 ogous expression of human KCNH2 channels and TRbeta, but not TRalpha, receptors.

22 factors, encoded by the TRalpha (NR1A1) and TRbeta (NR1A2) genes, to regulate target gene expression

23 ugation utilized the E3 ligase PIASxbeta and TRbeta-SUMO conjugation utilized predominantly PIAS1.

24 t phenotypes exhibited by TRalpha1(PV/+) and TRbeta(PV/+) mice indicate that the in vivo functions of

25 owever, the in vivo functions of TRalpha and TRbeta are undefined.

26 Both TRalpha and TRbeta bound the full and the half-site ERE as monomers

27 t experiment, the inheritance of TRalpha and TRbeta genotypes was determined for metamorphic and non

28 We analyzed involvement of TRalpha and TRbeta in neural cell proliferation during metamorphosis

29 by conjugation of small SUMO to TRalpha and TRbeta plays an important role in triiodothyronine (T3)

30 of the ligand-binding domain of TRalpha and TRbeta was cloned and sequenced for DNA samples from 14

31 the disruption of DNA binding of TRalpha and TRbeta, most notably heart rate, body temperature, blood

32 Ralpha, beta and gamma, RXRbeta, TRalpha and TRbeta, to bind various EREs in vitro .

33 an antibody that recognizes both TRalpha and TRbeta, we found that TR binding to the TRbeta promoter

34 nce variation was found for both TRalpha and TRbeta, with several nonsynonomous substitutions that pr

35 ne receptor isotypes, designated TRalpha and TRbeta.

36 s that are encoded by two genes, TRalpha and TRbeta.

37 s that are encoded by two genes, TRalpha and TRbeta.

38 encoding the related receptors, TRalpha and TRbeta.

39 of which there are two subtypes, TRalpha and TRbeta.

40 activate the wild-type receptors TRalpha and TRbeta.

41 mediated by TH receptor alpha (TRalpha) and TRbeta.

42 yroid hormone nuclear receptors TRalpha1 and TRbeta (the main thyroid hormone-binding isoforms) resul

43 ce that functional loss of both TRalpha1 and TRbeta genes promotes tumor development and metastasis.

44 ha(o/o), whereas they were similar in WT and TRbeta(-/-) mice, supporting the notion that TRalpha1 is

45 These studies indicate that NF-Y and TRbeta functionally interact to confer T3 control to the

46 gative mutant thyroid hormone receptor beta (TRbeta(PV/PV) mice) spontaneously develop follicular thy

47 gative mutant thyroid hormone receptor beta (TRbeta(PV/PV) mouse) spontaneously develop follicular th

48 gative mutant thyroid hormone receptor beta (TRbeta(PV/PV) mouse) that spontaneously develops a folli

49 ations of the thyroid hormone receptor beta (TRbeta) gene cause resistance to thyroid hormone (RTH).

50 ations in the thyroid hormone receptor beta (TRbeta) gene manifest resistance to thyroid hormone (RTH

51 ations in the thyroid hormone receptor beta (TRbeta) gene result in resistance to thyroid hormone.

52 ations in the thyroid hormone receptor beta (TRbeta) gene that cannot bind steroid receptor coactivat

53 domain of the thyroid hormone receptor beta (TRbeta) lead to resistance to thyroid hormone (RTH).

54 1 expression: thyroid hormone receptor beta (TRbeta), retinoid X receptor (RXR), and PPARalpha.

55 iganded human thyroid hormone receptor beta (TRbeta).

56 are the up-regulation of T(3) receptor beta (TRbeta; autoinduction) and BTEB1 (basic transcription el

57 gative mutant thyroid hormone receptor-beta (TRbeta(PV/PV) mice) spontaneously develop follicular thy

58 bution of the thyroid hormone receptor-beta (TRbeta) in living cells, utilizing fusions to the green

59 suggest that thyroid hormone receptor-beta (TRbeta) mutations could increase the risk of mammary tum

60 ation of the thyroid hormone receptor beta1 (TRbeta) appears to be associated with cancer onset and p

61 to compete for transcriptional silencing by TRbeta, indicating that the association of the LBD with

62 mouse model of follicular thyroid carcinoma (TRbeta(PV/PV) mice).

63 LBD peptide to a reaction mixture containing TRbeta led to a complete reversal of receptor-mediated t

64 By contrast, TRbeta was expressed predominantly outside of neurogenic

65 In contrast, TRbeta isoforms are not involved, because Purkinje cells

66 nally, we confirm that TRE-binding-defective TRbeta leads to disruption of the hypothalamic-pituitary

67 er but which is typically caused by dominant TRbeta mutants that are transcriptional inhibitors.

68 e labeled with terbium (fluorescence donor), TRbeta.RXRalpha heterodimer, and fluorescein-labeled NR

69 se relatives in THRB and NR1D2, which encode TRbeta and Rev-ErbAbeta, these beta isoforms do not shar

70 rboring a mutation in the Thrb gene encoding TRbeta (Thrb(PV) mouse).

71 radation of beta-catenin in cells expressing TRbeta via proteasomal pathways.

72 e methylsulfonylnitro group is essential for TRbeta antagonism.

73 however, results from a gain of function for TRbeta(PV) that stabilizes beta-catenin despite the pres

74 These data define in vivo functions for TRbeta and indicate that specificity in T3 signalling is

75 These findings suggest a unique role for TRbeta that cannot be substituted by TRalpha in the T3-d

76 ear compartment of cultured tumor cells from TRbeta(PV/PV) mice, but cytoplasmic p85alpha/PV or p85al

77 nvolved, because Purkinje cells derived from TRbeta-/- mice show the same T3 responsiveness as wild-t

78 nce of T3, beta-catenin was dissociated from TRbeta-beta-catenin complexes but not from TRbetaPV-beta

79 Intriguingly, loss-of-function TRbeta mutations cause deafness in mice and humans.

80 PTEN in thyroid carcinogenesis, we generated TRbeta(PV/PV) mice haploinsufficient for Pten (TRbeta(PV

81 ) by a nuclear receptor for thyroid hormone, TRbeta, acting rapidly at the plasma membrane through ph

82 PV) mice (a model of RTH) expressing a human TRbeta mutant (PV) with mice expressing a mutant Ncor1 a

83 treatment of T47D extracts with immobilized TRbeta LBD depleted the extract of the coactivator funct

84 ould contribute to thyroid carcinogenesis in TRbeta(PV/PV) mice.

85 g in constitutive activation of cyclin D1 in TRbeta(PV/PV) mice.

86 nd mice resistant to TH due to deficiency in TRbeta (TRbeta(-/-)).

87 nogenesis progressed significantly faster in TRbeta(PV/PV) mice with PPARgamma insufficiency from inc

88 ivation was further increased by two-fold in TRbeta(PV/PV)Pten(+/-) mice thyroids, leading to increas

89 cal progression, metastasis and histology in TRbeta(PV/PV)/Akt1(+/+) (PVPV-Akt1WT) and TRbeta(PV/PV)/

90 currence of metastasis spread to the lung in TRbeta(PV/PV)Pten(+/-) mice, thereby significantly reduc

91 entified overexpression of cyclin D1 mRNA in TRbeta(PV/PV) but not in TRalpha1(-/-) TRbeta(-/-) mice.

92 e/retinoblastoma protein/E2F pathway only in TRbeta(PV/PV) mice.

93 ses in TRalpha(o/o) and smaller responses in TRbeta(-/-) as compared with WT mice.

94 id hormone (T3) repressed STAT5 signaling in TRbeta-expressing cells through decreasing STAT5-mediate

95 eta-Catenin signaling was repressed by T3 in TRbeta-expressing cells through decreasing beta-catenin-

96 l gene expression correlates with increasing TRbeta levels.

97 are unable to lower lipids without inducing TRbeta-mediated suppression of the THA.

98 clear export of TRalpha and another isoform, TRbeta, is CRM1-independent.

99 The TH-inducible TR isoform, TRbeta, is expressed ubiquitously in the tail, but espec

100 The liganded TRbeta repressed cyclin D1 expression via tethering to t

101 ed by the direct interaction of the liganded TRbeta with steroid receptor coactivator 3 (SRC-3), whic

102 1, an oncogene, is regulated by the liganded TRbeta.

103 erse recruitment mechanism in which liganded TRbeta recruits corepressors to inhibit PLA2g2a expressi

104 DNA binding is not essential for maintaining TRbeta within the nucleus.

105 In this model, TRbeta signaling endowed DCs with the ability to stimula

106 port that targeted inactivation of the mouse TRbeta gene results in goitre and elevated levels of thy

107 This mutant mouse (TRbeta(PV/PV) mouse) provides an unusual opportunity to

108 Rbeta(PV/PV) mouse harbors a knock-in mutant TRbeta gene (TRbetaPV mutant) that spontaneously develop

109 ecular basis underlying the action of mutant TRbeta in vivo, we generated mice with a targeted mutati

110 The mutant TRbeta(H435A) is nonresponsive to physiological concentr

111 beta-catenin, via association with a mutated TRbeta, represents a novel activating mechanism of the o

112 We recently found that a dominantly negative TRbeta mutant (PV) that causes a genetic disease, resist

113 the cerebellum of TRalpha(PV/+) mice but not TRbeta(PV/PV) mice.

114 I have identified two novel TRbeta isoforms that are expressed widely and result fro

115 K1 gene expression in TH receptor beta-null (TRbeta(-/-)) mice.

116 ing the entire LBD (positions 145 to 456) of TRbeta.

117 Interestingly, in the brain, the absence of TRbeta may not mimic the defects often associated with d

118 It is unclear how the actions of TRbeta mutants are modulated in vivo to affect the manif

119 nce NCoR is known to modulate the actions of TRbeta mutants in vivo and in vitro, we asked whether NC

120 of Thrb-/- mice suggests that antagonism of TRbeta-mediated pathways underlies the disorder of the p

121 for inhibitors that block the association of TRbeta with steroid receptor coactivator 2 (SRC2), we id

122 versibly to Cys-298 within the AF-2 cleft of TRbeta to disrupt SRC2 association.

123 asic carboxylate-binding arginine cluster of TRbeta.

124 Using the offspring from the cross of TRbeta(PV/+) and PPARgamma(+/-) mice, we found that thyr

125 ivo by using the offspring from the cross of TRbeta(PV/PV) and SRC-3(-/-) mice.

126 hormone-induced (T3-induced) degradation of TRbeta, PTTG1 proteins were degraded by the proteasomal

127 TRalpha 1 reduced them, whereas deletion of TRbeta actually increased them.

128 We found that expression of TRbeta increases NCoR levels and that this induction is

129 was disrupted by heterologous expression of TRbeta receptors with mutations in the ligand-binding do

130 ome inhibit both T3 binding and formation of TRbeta homodimers on thyroid hormone response elements.

131 asm and that protein-protein interactions of TRbeta with various cofactors, rather than specific DNA

132 accumulation of beta-catenin by mutations of TRbeta in vivo.

133 By mutating defined regions of TRbeta, we found that both nuclear corepressor and retin

134 hyronine induced a nuclear reorganization of TRbeta.

135 To explore the role of TRbeta mutants in vivo in breast tumor development and p

136 Specifically we asked why a small subset of TRbeta mutations that arise in resistance to thyroid hor

137 Sumoylation of TRbeta was ligand-dependent, and sumoylation of TRalpha

138 ids(451-456) in the extreme COOH terminus of TRbeta resulted in a receptor that retained the ability

139 xpression correlates positively with that of TRbeta.

140 TRalpha1(PV/+) mice was unique from those of TRbeta(PV/+) mice.

141 notypes of TRalpha1(PV/+) mice with those of TRbeta(PV/+) mice.

142 roliferation and survival in the thyroids of TRbeta(PV/PV)Pten(+/-) mice.

143 reased caspase-3 activity in the thyroids of TRbeta(PV/PV)Pten(+/-) mice.

144 Treatment of TRbeta(PV/PV) mice with a PPARgamma agonist, rosiglitazo

145 is, was highly elevated in thyroid tumors of TRbeta(PV/PV) mice.

146 rred between transfected PR-B and TRalpha or TRbeta and vice versa in CV1 cells.

147 e with a mutation in either their TRalpha or TRbeta gene.

148 Ligand-occupied TRalpha or TRbeta, but not the unliganded receptor, strongly suppre

149 thyroid hormone (TH) receptors, TRalpha1 or TRbeta, is involved in the regulation of glucose utiliza

150 induction kinetics and thus may be partially TRbeta regulated.

151 urprisingly, however, we find that postnatal TRbeta-/- mice have a normal number of oligodendrocytes

152 PRMT2 also binds to ERbeta, PR, TRbeta, RARalpha, PPARgamma, and RXRalpha in a ligand-in

153 -response elements (TRE) in their promoters, TRbeta itself and TH/bZIP (TH-responsive basic leucine z

154 system to express green fluorescent protein-TRbeta in HeLa cells under tetracycline regulation, and

155 beta(PV/PV) mice haploinsufficient for Pten (TRbeta(PV/PV)Pten(+/-) mouse).

156 The degradation of PTTG1/TRbeta was activated by the direct interaction of the li

157 ated thyroid hormone receptor (TR) beta (PV; TRbeta(PV/PV) mouse) spontaneously developed TSH-omas.

158 e receptor beta(2), thyroid hormone receptor TRbeta), neurotransmitter transporters (glutamate/aspart

159 n within the LBD of the interfering receptor TRbeta was likely to interact with a mediator protein(s)

160 to a dominant-negative mutant T(3) receptor (TRbeta(PV)) that cannot bind T(3) and interferes with th

161 IRT1 interacted directly with T(3) receptor (TRbeta).

162 sociated with thyroid hormone beta receptor (TRbeta) as well as its mutant, designated PV.

163 sociated with thyroid hormone beta receptor (TRbeta) mutations which cluster in two regions (alphaalp

164 id carcinoma [thyroid hormone beta receptor (TRbeta)(PV/PV) mice].

165 ther recruited the thyroid hormone receptor (TRbeta) and another deacetylase, HDAC2.

166 This T3 receptor (TRbeta)-binding site differed considerably from consensu

167 S14 gene transcription through T3 receptors (TRbeta) binding distal thyroid hormone response elements

168 ther TRH, the beta isoforms of TH receptors (TRbeta KO), or both (double KO).

169 dition of triiodothyronine-bound recombinant TRbeta or a ligand binding domain (LBD) peptide(145-456)

170 ion decreased binding affinity, but retained TRbeta-selectivity.

171 hat the aberrant recruitment of NCOR1 by RTH TRbeta mutants leads to clinical RTH in humans.

172 r results establish an adjuvant effect of T3-TRbeta signaling in DCs, suggesting an immediately trans

173 betaPV) to establish the relevance of the T3-TRbeta system in vivo.

174 pha expression was considerably greater than TRbeta and there were significant differences in the rat

175 godendrocytes in their optic nerves and that TRbeta-/- OPCs stop dividing and differentiate normally

176 In summary, our findings demonstrate that TRbeta rapidly shuttles between the nucleus and the cyto

177 and heterokaryon analysis demonstrated that TRbeta rapidly shuttles between the nuclear and the cyto

178 The findings that TRbeta mutants affect PPARgamma functions through domina

179 ro and in vivo binding assays, we found that TRbeta bound directly to the PLA2g2a promoter as a heter

180 Comparison of the structures reveals that TRbeta accommodates T(4) through subtle alterations in t

181 We next show that TRbeta-targeted ribozymes can inhibit T3-induced transcr

182 Previous studies suggested that TRbeta receptors may mediate the effect of TH on oligode

183 This finding suggests that TRbeta mutants could crosstalk with PPARgamma-signaling

184 effect of TRalpha2 in tissues expressing the TRbeta isoforms.

185 TR agonists selective for the TRbeta isoform exhibit modest cardiac sparing in rodents

186 In the TRbeta crystal structure this helix 3 residue is surface

187 nerated mice with a targeted mutation in the TRbeta gene (TRbetaPV; PV, mutant thyroid hormone recept

188 hat seen in mice with a null mutation in the TRbeta gene.

189 f RTH that harbors a knockin mutation of the TRbeta gene (TRbetaPV mouse), we investigated the effect

190 e determined x-ray crystal structures of the TRbeta LBD in complex with T(3) and T(4) at 2.5-A and 3.

191 and TRbeta, we found that TR binding to the TRbeta promoter is indeed constitutive.

192 In drastic contrast to the TRbeta(PV/+) mice, which do not exhibit a growth abnorma

193 l proliferation; whereas, treatment with the TRbeta-selective agonists GC1 or GC24 did not.

194 These TRbeta mutants function in a dominant-negative fashion t

195 This TRbeta(PV/PV) mouse harbors a knock-in mutant TRbeta gen

196 T3 binding to TRbeta increased DC viability and augmented DC migration

197 In contrast to TRbeta(PV/+) mice, which have a hyperactive thyroid, TRa

198 Mutations to TRbeta that reduce or abolish ligand-dependent transacti

199 By using an antibody specific to TRbeta,TRbeta binding increases at both promoters in res

200 /bZIP TRE with 4-fold lower affinity than to TRbeta TRE.

201 It is unknown whether TRalpha, TRbeta or other receptors are targets for inhibition in

202 NA in TRbeta(PV/PV) but not in TRalpha1(-/-) TRbeta(-/-) mice.

203 hat mice deficient in all TRs (TRalpha1(-/-) TRbeta(-/-)) had similarly increased T3 and TSH levels,

204 deletion of all functional TRs (TRalpha1(-/-)TRbeta(-/-) mice).

205 ymes are active in vitro against transcribed TRbeta message and in vivo against a TRbeta-luciferase f

206 resistant to TH due to deficiency in TRbeta (TRbeta(-/-)).

207 heir reduced Ka and they inhibited wild-type TRbeta action in a dominant negative manner.

208 how that the actions of mutant and wild-type TRbeta in vivo are distinct.

209 Wild-type TRbeta was mostly nuclear in both the absence and presen

210 ssays show that the PV, similar to wild-type TRbeta, bound to the peroxisome proliferator response el

211 plasmic distribution compared with wild-type TRbeta; thus, site-specific DNA binding is not essential

212 tracts in which exogenously added unliganded TRbeta repressed the basal level of RNA polymerase II-dr

213 l molecular mechanism by which an unliganded TRbeta mutant acts to contribute to pituitary tumorigene

214 ased the shuttling by maintaining unliganded TRbeta within the nucleus.

215 atenin physically associated with unliganded TRbeta or TRbetaPV.

216 The molecular mechanism by which TRbeta mutants cause RTH has been postulated to be an in

217 f T3 to promote coactivator association with TRbeta, our experiments demonstrate a novel inverse recr

218 QH2's functionally orthogonal behavior with TRbeta(H435A) is preserved on the three consensus thyroi

219 dence of distant metastasis as compared with TRbeta(PV/PV) mice with SRC-3 (TRbeta(PV/PV)SRC-3(+/+) m

220 tly reducing their survival as compared with TRbeta(PV/PV)Pten(+/+) mice.

221 The betaTP TRE forms specific complexes with TRbeta.

222 To identify factors that cooperate with TRbeta during human erythroid terminal differentiation,

223 r 1 (Ncor1) allele that cannot interact with TRbeta, termed NCoRDeltaID, have low TH levels and norma

224 However, PPARalpha interfered with TRbeta/RXRalpha binding to a TRE (DR+4).

225 rase assays from 293T cells transfected with TRbeta or LXRalpha expression plasmids show that TR, tog

226 Treatment with TRbeta agonists stimulated premature erythroblast differ

227 nsfected living tadpole brain with a Xenopus TRbeta promoter-EGFP plasmid and found that most EGFP ex