ライフサイエンスコーパス: HNF-4

1 s and contained hepatocyte nuclear factor-4 (HNF-4).

2 ptor (PXR), and hepatocyte nuclear factor 4 (HNF-4).

3 nuclear factors 1alpha and 4 (HNF-1alpha and HNF-4).

4 to confer promoter induction in response to HNF-4.

5 tocyte nuclear factor-1alpha (HNF-1alpha) or HNF-4.

6 the transcription factors HNF-1, vHNF-1, and HNF-4.

7 full DNA binding affinity of the full-length HNF-4.

8 ecessary for dimerization and DNA binding of HNF-4.

9 y mechanism of transcriptional activation by HNF-4.

10 HNF-4alpha2, as well as naturally-occurring HNF-4.

11 sed by plasmids expressing either isoform of HNF-4.

12 and subsequent transcriptional activation by HNF-4.

13 and regulate the activity of PPARs, LXRs and HNF-4.

14 h expression plasmids encoding HNF-1alpha or HNF-4.

15 new insights into the regulatory function of HNF-4.

16 re deficient in expression of HNF-1alpha and HNF-4.

17 ith the binding sites of Sp1 (-764/-742) and HNF-4 (-736/-714).

18 functional cross-talk between human PXR and HNF-4, a key hepatic activator of genes involved in bile

19 ion of the transcription cycle revealed that HNF-4 activated transcription by facilitating assembly o

20 HNF-4 activates several hepatocyte-specific genes, inclu

21 This interaction likely involves primary HNF-4 activation function 2 (AF-2)-dependent interaction

22 Our data suggest that CAR inhibits HNF-4 activity by competing with HNF-4 for binding to th

23 ription systems that faithfully recapitulate HNF-4 activity.

24 2) which work synergistically to confer full HNF-4 activity.

25 intestinal-derived cell line IEC-6 with the HNF-4 adenovirus resulted in a greater than 20-fold incr

26 The inhibitory effect of region F on the HNF-4 AF-2 activity is a unique feature among members of

27 The two activating functions of HNF-4, AF-1 and AF-2, interact with the N terminus and t

28 alpha but induce c-Jun, which in turn blocks HNF 4 alpha recruitment of PGC-1 alpha to the CYP7A1 chr

29 le coenzyme A thioesters of PUFAs antagonize HNF-4 alpha action.

30 HNF-4 alpha, mutations in the gene encoding HNF-4 alpha being another cause of MODY (MODY1).

31 egion of the protein that may play a role in HNF-4 alpha dimerization and DNA binding.

32 (i) ACBP interaction with HNF-4 alpha elicited significant changes in secondary st

33 The information on the sequence of the HNF-4 alpha gene and its promoter region will facilitate

34 The results suggest that mutations in the HNF-4 alpha gene may cause early-onset NIDDM/MODY in Jap

35 ganization and partial sequence of the human HNF-4 alpha gene.

36 rmolecular distance of 53 A between ACBP and HNF-4 alpha in rat hepatoma cell nuclei.

37 In summary, ACBP physically interacted with HNF-4 alpha in vitro and in intact cells, although ACBP

38 ive lines of evidence showed that ACBP bound HNF-4 alpha in vitro and in the nucleus of intact cells.

39 HNF-4 alpha is a nuclear receptor that is critical for t

40 This decrease in HNF-4 alpha is primarily the result of a posttranscripti

41 IL-1 beta resulted in a decrease in HNF-4 alpha levels in HepG2 cells.

42 ists or proteasome inhibitors might increase HNF-4 alpha protein levels in the acute-phase response,

43 We conclude that the decrease in HNF-4 alpha that occurs in vivo after the administration

44 tional significance of ACBP interaction with HNF-4 alpha was evidenced by mammalian two-hybrid and tr

45 (ii) ACBP and HNF-4 alpha were coimmunoprecipitated by antibodies to e

46 S-7 cells significantly colocalized ACBP and HNF-4 alpha within the nucleus and in the perinuclear re

47 Hepatocyte nuclear factor-4 alpha (HNF-4 alpha) is a member of the nuclear receptor superfa

48 cted with hepatocyte nuclear factor-4 alpha (HNF-4 alpha), a nuclear binding protein that regulates t

49 n factor, hepatocyte nuclear factor 4 alpha (HNF-4 alpha), in livers of rats.

50 f the individual triple fluorescent-labeled (HNF-4 alpha, ACBP, and luciferase) rat hepatoma cells sh

51 ession of a gene that is highly dependent on HNF-4 alpha, HNF-1 alpha, was reduced.

52 he binding site for the transcription factor HNF-4 alpha, mutations in the gene encoding HNF-4 alpha

53 ed fatty acyl coenzyme A thioesters activate HNF-4 alpha, while coenzyme A thioesters of PUFAs antago

54 epatoma cells enhanced transactivation of an HNF-4 alpha-dependent luciferase reporter plasmid by 3.2

55 BP expression level directly correlated with HNF-4 alpha-mediated transactivation in individual cells

56 tron microscopy detected ACBP within 43 A of HNF-4 alpha.

57 (alpha and beta), hepatic nuclear factor-4 (HNF-4)alpha and sterol regulatory element binding protei

58 ment I4 (-732/-712), which was shown to bind HNF-4, also binds strongly ARP-1 and EAR-3, as well as R

59 eceptors are sufficient for interaction with HNF-4, although deletion results indicate that additiona

60 Therefore, HNF-4, an important regulator of liver-specific genes, p

61 HNF-4, an orphan member of the nuclear receptor superfam

62 cleotide determine the binding preference of HNF-4 and ARP-1 homodimers and RAR:RXR and PPAR:RXR hete

63 ar hormone receptors the interaction between HNF-4 and CBP is ligand-independent.

64 nobarbital treatment, whereas association of HNF-4 and coactivators, GRIP-1, p300, and PGC-1alpha, wi

65 ted intermediary factor jointly recruited by HNF-4 and HNF-3 participates in activation of the apoAI

66 The amount of HNF-4 and HNF-3 was decreased posttranscriptionally by 8

67 In non-hepatic CV-1 cells, HNF-4 and HNF-3beta activated this minimal enhancer syne

68 strong synergistic relationships with HNF-1, HNF-4 and HNF-3beta and with C/EBPbeta.

69 tected organ-specific expression of albumin, Hnf-4 and Igfbp-1, in a set of mouse organ cDNA populati

70 We conclude that HNF-4 and NF-Y play crucial roles in modulating the acti

71 and -128 and their cognate binding proteins, HNF-4 and NF-Y, respectively, were identified.

72 may depend on the direct association between HNF-4 and NF-Y.

73 sociation with the nuclear hormone receptors HNF-4 and PPAR-alpha, respectively.

74 on experiments transcriptional activation by HNF-4 and PPAR:RXR and repression by ARP-1 correlated wi

75 fic transcription factors that interact with HNF-4 and PPAR:RXR determine the specificity of transcri

76 determined whether an element that binds to HNF-4 and PPAR:RXR with equal affinity functions as an H

77 BP acts as a transcriptional coactivator for HNF-4 and provide new insights into the regulatory funct

78 HNF-4 and Sp1 appear to bind site 1 in a mutually exclus

79 Methylation interference assays reveal that HNF-4 and Sp1 contact adjacent sites with minor overlap.

80 ity, indicating that the interaction between HNF-4 and the intervening nucleotide(s) is critical for

81 We also show that HNF-4 and TRAP/SMCC/Mediator can interact physically.

82 -80 to -70 and of hepatocyte nuclear factor HNF-4 (and ARP-1) to the segment from -148 to -127 of th

83 tocyte nuclear factors (especially HNF-1 and HNF-4) and CCAAT/enhancer-binding protein (C/EBPbeta) ar

84 ously that hepatocyte nuclear factor-4alpha (HNF-4) and the alpha(1)-fetoprotein transcription factor

85 orphan receptor hepatocyte nuclear factor 4 (HNF-4) and the retinoid X receptor (RXR) by at least two

86 ibodies against hepatocyte nuclear factor-4 (HNF-4) and transactivation of the HGFL promoter by a HNF

87 ription factor, hepatocyte nuclear factor-4 (HNF-4), and a ubiquitous transcription factor, Spl, are

88 iption factors including HNF-1 alpha, HNF-3, HNF-4, and C/EBP beta, and the more ubiquitously express

89 t activate gene expression in the absence of HNF-4, and dominant negative forms of HNF-4 prevent tran

90 ha-fetoprotein by day 7, and expressed CK18, HNF-4, and HNF-1alpha on days 14-28.

91 r is complex, spanning the 128-366 region of HNF-4, and it cannot be further dissected without impair

92 ast three host transcription factors: HNF-1, HNF-4, and Oct-1.

93 r PGC-1 enhanced transcriptional activity of HNF-4, and this enhancement was suppressed by rifampicin

94 On the basis of these results, HNF-4 appears to activate transcription at two distinct

95 t B (-87/-72) binds strongly, in addition to HNF-4, ARP-1, EAR-2, and EAR-3, heterodimers of RXRalpha

96 Within the DH2 region, an HNF-4/ARP-1 binding site was demonstrated by gel retarda

97 permutation analysis showed that full-length HNF-4 bent DNA by approximately 80 degrees while the DBD

98 es derived from the substitution that affect HNF-4 binding in vitro.

99 sly identified footprint B which contains an HNF-4 binding site (-87/-63).

100 gonucleotide probe representing an essential HNF-4 binding site, C3P contained in the human apo CIII

101 The mutation in the three HNF-4 binding sites of the apoA-I promoter/apoCIII enhan

102 bility shift assay confirmed the presence of HNF-4 binding sites upstream of A. aegypti vg and vcp, t

103 tudies, rifampicin treatment did not inhibit HNF-4 binding to the native promoters of CYP7A1 and CYP8

104 ence that is an hepatocyte nuclear factor 4 (HNF-4) binding site within the factor VII promoter (ACTT

105 arboxykinase gene that contains a functional HNF-4-binding site and is central to hepatic gluconeogen

106 suggest the binding of HNF-4 to the proximal HNF-4-binding site directs the basal transcription of th

107 HeLa cells, whereas mutations in the distal HNF-4-binding site had no effect.

108 nting with recombinant HNF-4 located another HNF-4-binding site in the distal region, -89 to -54.

109 Mutations in the CAATT or the proximal HNF-4-binding site significantly reduced the promoter ac

110 proximity between the CAATT and the proximal HNF-4-binding site suggested that a direct contact betwe

111 a HNF-4 cDNA expression vector suggest that HNF-4 binds to the -135/-105 region and is responsible f

112 Hepatic nuclear factor-4 (HNF-4) binds and activates the 12alpha-hydroxylase promo

113 n previously to bind ARP-1 and EAR-3 but not HNF-4, binds strongly heterodimers of RXRalpha with eith

114 We also demonstrate that HNF-4 can transactivate the Factor X promoter in HeLa ce

115 nd transactivation of the HGFL promoter by a HNF-4 cDNA expression vector suggest that HNF-4 binds to

116 ceptors (RXRs), hepatocyte nuclear factor 4 (HNF-4), chicken ovalbumin upstream promoter transcriptio

117 equence for HNF-1alpha, HNF-1beta, HNF-3, or HNF-4 completely restored the PKA response.

118 HNF4(E276Q) has lost its ability to bind to HNF-4 consensus binding sites and activate transcription

119 The 360-366 region of HNF-4 contains a motif that is highly conserved among tr

120 We have previously shown that HNF-4 contains transcription activation functions at the

121 In this report, we show that HNF-4 contains two transactivation domains, designated A

122 Thus, HNF-1alpha and HNF-4 control both chromatin structure and gene activity

123 Bf-CAT is not expressed in cells that lack HNF-4 (CV-1).

124 Hepatocyte nuclear factor 4 (HNF-4) defines a new subgroup of nuclear receptors that

125 tly showed that hepatocyte nuclear factor 4 (HNF-4) defines a unique subclass of nuclear receptors th

126 F-4 was not sufficient for activation, since HNF-4 deletion derivatives lacking AF-2 bound TFIIB.

127 Thus, HNF-4 deletion mutants lacking the 361-465 region bind e

128 tor PC4 display relatively robust activator (HNF-4)-dependent activity, which, nonetheless, can be fu

129 Hepatocyte nuclear factor 4 (HNF-4), derived from HepG2, mouse liver and kidney or ce

130 In gel mobility shift assays, DN-HNF-4 did not bind an oligonucleotide probe representing

131 Activation by HNF-4 did not exhibit a ligand requirement, but phosphor

132 e have generated a dominant negative form of HNF-4 (DN-HNF-4) that contains a defective DNA-binding d

133 These results indicate that the HNF-4 DNA binding domain is distinct from that of other

134 These results indicate that HNF-4 does regulate apolipoprotein AI and CIII mRNA expr

135 In transfected HepG2 cells, DN-HNF-4 dramatically reduced constitutive transcriptional

136 ements within the apoCIII promoter that bind HNF-4, either of which are sufficient to confer promoter

137 Furthermore, specific complementation of Hnf-4(-/-) embryos with tetraploid-derived Hnf-4(+/+) VE

138 To decipher the mechanism whereby HNF-4 enhances apoAI gene transcription, we have reconst

139 Using Hnf-4(-/-) ES cells we demonstrate that HNF-4 is a key r

140 focused on the coactivator requirements for HNF-4, especially for the multicomponent TRAP/SMCC/Media

141 These findings indicate that HNF-4 exerts a major positive regulatory effect on facto

142 Transactivation studies with an HNF-4 expression plasmid in HeLa cells also demonstrate

143 Cotransfections with ATF-2 and HNF-4 expression plasmids resulted in additive transacti

144 AR inhibits HNF-4 activity by competing with HNF-4 for binding to the DR1 motif and to the common coa

145 shift assays revealed that CAR competes with HNF-4 for binding to the DR1 motif in the CYP7A1 promote

146 GC-1alpha, indicating that CAR competes with HNF-4 for these coactivators.

147 HNF-4gamma, the other HNF-4 form highly expressed in intestine, is much less s

148 ptors and that the determinants that prevent HNF-4 from heterodimerizing with RXR lie outside the DNA

149 ree isoforms of hepatocyte nuclear factor-4 (HNF-4) from the mosquito Aedes aegypti, designated AaHNF

150 we showed that the 24 N-terminal residues of HNF-4 function as an acidic transcriptional activator, t

151 odies, we demonstrate a strong dependence of HNF-4 function on this coactivator.

152 erstanding the molecular mechanisms by which HNF-4 functions, we have established in vitro transcript

153 ion of the human SHP promoter defined HNF-3, HNF-4, GATA, and AP-1 sites as important for basal activ

154 DN-HNF-4 had no effect on the binding of PPARgamma-RXRalpha

155 Our results suggest that HNF-4 has strong synergistic relationships with HNF-1, H

156 the binding of hepatocyte nuclear factor 4 (HNF-4), HNF-3, and fetoprotein factor to the precore/cor

157 g the liver-enriched trans activators HNF-1, HNF-4, HNF-3 alpha, and HNF-3 beta was not affected in a

158 Regulation of HNF-4/HNF-1 expression by HNF-3alpha and HNF-3beta was s

159 alone nor binds it as a dimer with wild-type HNF-4 (HNF4.wt).

160 RXRalpha/RARalpha heterodimers and HNF-4 homodimers bind to DR-1 motifs on elements B and I

161 To assess the roles of HNF-1alpha and HNF-4 in gene activation and chromatin remodeling, we tr

162 eLa cells also demonstrate the importance of HNF-4 in promoting transcription in non-hepatocyte deriv

163 a ligand requirement, but phosphorylation of HNF-4 in the in vitro transcription system was observed.

164 n initial step in characterizing the role of HNF-4 in the regulation of metabolism, we have generated

165 PGC-1 directly interacted with both PXR and HNF-4 in vitro.

166 viously been shown to be highly sensitive to HNF-4-induced transcription.

167 Although HNF-4 interacts with SHP, it is not involved in SHP-medi

168 HNF-4 interacts with the N-terminal region of CBP (amino

169 However, co-transfection of HNF-4 into CV-1 cells drives Bf-CAT expression and repro

170 sing Hnf-4(-/-) ES cells we demonstrate that HNF-4 is a key regulator of tissue-specific gene express

171 These results indicate that DN-HNF-4 is a selective dominant negative mutant which form

172 a cell lines, HepG2 and Hep3B, indicate that HNF-4 is also involved in the regulation of apolipoprote

173 l-length receptor, the DNA binding domain of HNF-4 is capable of heterodimerizing with that of the re

174 AI and CIII mRNA expression and suggest that HNF-4 is critical for intestinal apolipoprotein AI expre

175 eport, the role of the LBD in DNA binding by HNF-4 is further investigated by using electrophoretic m

176 I mRNA by 80%, demonstrating that endogenous HNF-4 is necessary for apolipoprotein CIII expression.

177 ggesting that the mere recruitment of CBP by HNF-4 is not sufficient for enhancement of gene expressi

178 the putative ligand binding domain (LBD) of HNF-4 is responsible for dimerization in solution and pr

179 Since expression of the transcription factor HNF-4 is restricted to the VE during this phase of devel

180 FTF and not HNF-4 is the factor involved in regulation of 12alpha-hy

181 Hepatocyte nuclear factor-4 (HNF-4) is a liver-enriched transcription factor that is

182 The hepatocyte nuclear factor 4 (HNF-4) is a member of the nuclear receptor superfamily a

183 uclear receptor hepatocyte nuclear factor 4 (HNF-4) is an important regulator of several genes involv

184 Hepatocyte nuclear factor 4 (HNF-4) is an orphan intracellular receptor that appears

185 uclear receptor hepatocyte nuclear factor 4 (HNF-4) is required for development and maintenance of th

186 ey hepatic factor, hepatic nuclear factor-4 (HNF-4), is crucial for the expression of many of these g

187 Dimerization of AaHNF-4c with other mosquito HNF-4 isoforms or with mammalian HNF-4 prevents binding

188 Overexpression of HNF-4 leads to a 7.4-fold increase in apolipoprotein CII

189 binding sites for hepatocyte nuclear factor (HNF-4), liver X receptor (LXR) and alpha(1)-fetoprotein

190 DNase I footprinting with recombinant HNF-4 located another HNF-4-binding site in the distal r

191 dy, we show that the dimerization domains of HNF-4 map to both the DNA binding and the ligand binding

192 ested that a direct contact between NF-Y and HNF-4 might be important.

193 role in this process emerged from studies of Hnf-4(-/-) mouse embryos which fail to undergo normal ga

194 affect simultaneous binding of HNF-3beta and HNF-4 nor did it influence their functional synergy.

195 However, the effect of HNF-4 on apolipoprotein AI expression is much more drama

196 r dimeric nuclear receptor complexes such as HNF-4 or ARP-1.

197 The HNF-4 orphan receptor is a member of the nuclear recepto

198 sential for EnII function in vivo, and (iii) HNF-4 plays a demonstrable but adjunctive role in EnII f

199 nce of HNF-4, and dominant negative forms of HNF-4 prevent transcriptional activation by CBP, suggest

200 er mosquito HNF-4 isoforms or with mammalian HNF-4 prevents binding to the HNF-4 response element.

201 DY1 phenotype is due to a loss of functional HNF-4 protein that is aggravated in tissues that express

202 a stop codon at amino acid 268 in the LBD of HNF-4 (Q268X) that leaves the DBD intact, suggesting tha

203 ivation activity; and 2) it occupies the FTF/HNF-4 recognition site within the 7alpha- and 12alpha-hy

204 xtract from HeLa cells, which do not contain HNF-4, recombinant HNF-4 stimulated transcription from b

205 Here, we show that HNF-4 recruits the CREB-binding protein (CBP) coactivato

206 fection with the dominant negative mutant of HNF-4 reduces the level of apolipoprotein CIII mRNA by 8

207 this phase of development, we proposed that HNF-4-regulated gene expression in the VE creates an env

208 uclear receptor hepatocyte nuclear factor 4 (HNF-4) regulates the expression of many liver-specific g

209 PPAR:RXR with equal affinity functions as an HNF-4 response element or PPAR response element.

210 with mammalian HNF-4 prevents binding to the HNF-4 response element.

211 n bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements.

212 Recruitment of CBP by HNF-4 results in an enhancement of the transcriptional a

213 liver and kidney or cell-free translation of HNF-4 RNA, is the nuclear protein that preferentially bi

214 HNF-4 selected for direct repeat-like elements with eith

215 omain (DBD) alone or the DBD plus the LBD of HNF-4 showed that dimerization via the DBD was sufficien

216 ts that ligand-activated PXR interferes with HNF-4 signaling by targeting the common coactivator PGC-

217 pends on interactions between the HNF-1alpha/HNF-4 signaling cascade and the serpin LCR.

218 viral RNA synthesis or DNA replication, and HNF-4 site lesions produced a modest reduction of pregen

219 HNF-4 site mutants were replication competent but may di

220 n EnII, mutations in either the HNF-1 or the HNF-4 site strongly reduced CAT activity, while ablation

221 lso demonstrate that neither the LXR nor the HNF-4 sites are involved in bile acid-mediated regulatio

222 The DexRE-1 and HNF-4 sites are not ligand-responsive, but are essential

223 s accessory factors bound at the DexRE-1 and HNF-4 sites.

224 n promoters of genes that contain functional HNF-4 sites.

225 lls, which do not contain HNF-4, recombinant HNF-4 stimulated transcription from basal promoters link

226 F-4a and AaHNF-4b are typical members of the HNF-4 subfamily of nuclear receptors with high amino aci

227 ssues that express relatively low amounts of HNF-4, such as pancreas.

228 uld be reversed in the presence of ATF-2 and HNF-4, suggesting that ATF2 and possibly Jun/ATF-2 heter

229 ing sites were efficiently transactivated by HNF-4, suggesting that these two factors contribute inde

230 SHP interacts with the same HNF-4 surface recognized by transcriptional coactivators

231 which can otherwise be occupied by a factor (HNF-4) that cannot be suppressed by SHP.

232 erated a dominant negative form of HNF-4 (DN-HNF-4) that contains a defective DNA-binding domain.

233 forms defective heterodimers with wild-type HNF-4, thereby preventing DNA binding and subsequent tra

234 The apoAI gene is activated by HNF-4 through a nuclear receptor binding element (site A

235 The binding of in vitro translated HNF-4 to immobilized NF-YA and in vitro translated NF-YA

236 ow that the mutation disrupts the binding of HNF-4 to its cognate binding site.

237 These results suggest the binding of HNF-4 to the proximal HNF-4-binding site directs the bas

238 contribution of hepatocyte nuclear factor 4 (HNF-4) to endogenous apolipoprotein AI and CIII mRNA exp

239 Expression of CAR inhibited HNF-4 transactivation of CYP7A1, a key gene in bile acid

240 enes, we examined whether CAR could suppress HNF-4 transactivation.

241 coactivators, potentiated CAR inhibition of HNF-4 transactivation.

242 her show a TRAP/SMCC/Mediator-dependence for HNF-4 transcriptional activation from chromatin template

243 ced the promoter activity in Hep3B cells and HNF-4-transfected HeLa cells, whereas mutations in the d

244 he hepatocyte-enriched factors HNF-3beta and HNF-4, two transcription factors essential for apoAI enh

245 f Hnf-4(-/-) embryos with tetraploid-derived Hnf-4(+/+) VE rescues their early developmental arrest,

246 Although HNF-4 was able to transactivate the wild-type factor VII

247 and in vitro translated NF-YA to immobilized HNF-4 was also detected.

248 nteraction between the A-subunit of NF-Y and HNF-4 was detected by a yeast two-hybrid system.

249 The activation function of HNF-4 was localized to a domain displaying strong homolo

250 However, recruitment of TFIIB by HNF-4 was not sufficient for activation, since HNF-4 del

251 Functional HNF-4 was purified to homogeneity from a bacterial expre

252 al vectors and a dominant negative mutant of HNF-4, we have examined the contribution of hepatocyte n

253 f the binding and activation requirements of HNF-4, we performed genetic analysis of the apoCIII prom

254 the DNA sequence recognition requirements of HNF-4, we utilized PCR-based binding site selection.

255 These data show that interaction of HNF-4 with polymorphic variants of the upstream Bf promo