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Glucocorticoid Receptor-interacting Protein 1 Mediates Ligand-independent Nuclear Translocation and Activation of Constitutive Androstane Receptor in Vivo *

  • Gyesik Min
    Footnotes
    Affiliations
    From the Department of Molecular & Integrative Physiology, College of Medicine at Urbana-Champaign, University of Illinois, Urbana, Illinois 61801
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  • J. Kim Kemper
    Footnotes
    Affiliations
    From the Department of Molecular & Integrative Physiology, College of Medicine at Urbana-Champaign, University of Illinois, Urbana, Illinois 61801
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  • Byron Kemper
    Correspondence
    To whom correspondence should be addressed: Dept. of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 S. Goodwin Ave., Urbana, IL 61801. Tel.: 217-333-1146; Fax: 217-333-1133;
    Affiliations
    From the Department of Molecular & Integrative Physiology, College of Medicine at Urbana-Champaign, University of Illinois, Urbana, Illinois 61801
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  • Author Footnotes
    * This work was supported by Grant GM39360 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
    ‡ These authors contributed equally to this work.
    § Present address: Chilam-Dong 150, Department of Microbiological Engineering, Jinju National University, Jinju-City 660-758, Gyeongsangnam-Do, Korea.
Open AccessPublished:May 08, 2002DOI:https://doi.org/10.1074/jbc.M200051200
      Phenobarbital (PB) induction ofCYP2B genes is mediated by translocation of the constitutively active androstane receptor (CAR) to the nucleus. Interaction of CAR with p160 coactivators and enhancement of CAR transactivation by the coactivators have been shown in cultured cells. In the present studies, the interaction of CAR with the p160 coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) was examined in vitro and in vivo. Binding of GRIP1 to CAR was shown by glutathione S-transferase (GST) pull-down and affinity DNA binding. N- or C-terminal fragments of GRIP1 that contained the central receptor-interacting domain bound to GST-CAR, but the presence of ligand increased the binding to GST-CAR of only the fragments containing the C-terminal region. In gel shift analysis, binding to CAR was observed only with GRIP1 fragments containing the C-terminal region, and the binding was increased by a CAR agonist and decreased by a CAR antagonist. Expression of GRIP1 enhanced CAR-mediated transactivation in cultured hepatic-derived cells 2–3-fold. In hepatocytes transfected in vivo, expression of exogenous GRIP1 alone induced transactivation of theCYP2B1 PB-dependent enhancer 15-fold, whereas CAR expression alone resulted in only a 3-fold enhancement in untreated mice. Remarkably, CAR and GRIP1 together synergistically transactivated the enhancer about 150-fold, which is approximately equal to activation by PB treatment. In PB-treated mice, expression of exogenous CAR alone had little effect, expression of GRIP1 increased transactivation about 2-fold, and with CAR and GRIP, a 4-fold activation was observed. In untreated mice, expression of GRIP resulted in nuclear translocation of green fluorescent protein-CAR. These results strongly suggest that a p160 coactivator functions in CAR-mediated transactivation in vivo in response to PB treatment and that the synergistic activation of CAR by GRIP in untreated animals results from both nuclear translocation and activation of CAR.
      CAR
      constitutive androstane receptor
      RXR
      retinoid X receptor
      PB
      phenobarbital
      PBRU
      PB-responsive unit
      SRC-1
      steroid hormone receptor coactivator-1
      TCPOBOP
      1,4-bis[2-(3,5-dichloropyridyloxy)]benzene
      GRIP
      glucocorticoid receptor interacting protein
      GST
      glutathioneS-transferase
      BSA
      bovine serum albumin
      NR
      nuclear receptor
      βRARE
      β-retinoic acid-responsive element
      In response to treatment with drugs or other xenobiotics, metabolism of the administered drug or other drugs is often increased (
      • Gonzalez F.J.
      ). Underlying the increase in most cases is an induction of the expression of cytochrome P450 genes. Different subsets of cytochrome P450 genes are induced by different chemicals. Recently, members of the nuclear receptor family that form heterodimers with RXR, including peroxisomal proliferator activating receptor α, pregnane X receptor/steroid X receptor, and CAR,1 have been identified as mediators of the cellular response to xenobiotics (reviewed in Ref.
      • Xie W.
      • Evans R.M.
      ). These nuclear receptors have relatively low specificity and affinity for their ligands so that they can be activated by a wide range of structurally diverse chemicals and thus comprise a broad response mechanism to xenobiotics.
      CAR has been identified as the mediator of induction ofCYP2B genes by the classical inducer of drug metabolism, PB. CAR was implicated in PB induction of CYP2B genes by the observation that CAR was selectively present in nuclear extracts from PB-treated animals and could bind to site with direct repeats separated by 4 base pairs (NR-1 and NR-2) in the CYP2B PB-responsive enhancer, termed PBRU or PB-responsive module (
      • Honkakoski P.
      • Zelko I.
      • Sueyoshi T.
      • Negishi M.
      ). In cultured cells, expression of CAR by transient or stable transfection could transactivate the PBRU or induce the expression of the endogenousCYP2B6 gene in HepG2 cells (
      • Honkakoski P.
      • Moore R.
      • Washburn K.A.
      • Negishi M.
      ,
      • Sueyoshi T.
      • Kawamoto T.
      • Zelko I.
      • Honkakoski P.
      • Negishi M.
      ,
      • Kim J.
      • Min G.
      • Kemper B.
      ,
      • Muangmoonchai R.
      • Smirlis D.
      • Wong S.C.
      • Edwards M.
      • Phillips I.R.
      • Shephard E.A.
      ). The loss of PB induction of Cyp2b genes in transgenic mice with a disrupted CAR gene provided conclusive evidence of an essential role for CAR in PB induction (
      • Wei P.
      • Zhang J.
      • Egan-Hafley M.
      • Liang S.
      • Moore D.D.
      ).
      CAR is unusual among the nuclear receptors in that it has relatively high constitutive activity (
      • Baes M.
      • Gulick T.
      • Choi H.-S.
      • Grazia M.
      • Martinoli G.
      • Simha D.
      • Moore D.D.
      ). The initial ligands identified for CAR, androstanes, inhibited rather than activated CAR so that CAR was considered constitutively active (
      • Forman B.M.
      • Tzameli I.
      • Choi H.-S.
      • Chen J.
      • Simha D.
      • Seol W.
      • Evans R.M.
      • Moore D.D.
      ). The concentrations of androstanes required for inhibition were higher than physiological concentrations, so it was initially unclear how PB induction could be mediated by such a constitutive nuclear receptor. This was clarified by the observation that CAR in untreated animals or primary cultures of hepatocytes is predominantly located in the cytoplasm of hepatocytes in contrast to continuously cultured cells where it is located in the nucleus (
      • Kawamoto T.
      • Sueyoshi T.
      • Zelko I.
      • Moore R.
      • Washburn K.
      • Negishi M.
      ). Treatment with PB resulted in translocation into the nucleus, which should be sufficient for transactivation of the PBRU because of its constitutive activity. Binding of PB to CAR was not detected, but binding of other PB-like ligands, such as TCPOBOP, was detected by several techniques, and activation of CAR by these ligands was implied by an increase in interaction with the coactivator SRC-1 in the presence of TCPOBOP (
      • Tzameli I.
      • Pissios P.
      • Schuetz E.G.
      • Moore D.D.
      ,
      • Moore L.B.
      • Parks D.J.
      • Jones S.A.
      • Bledsoe R.K.
      • Consler T.G.
      • Stimmel J.B.
      • Goodwin B.
      • Liddle C.
      • Blanchard S.G.
      • Willson T.M.
      • Collins J.L.
      • Kliewer S.A.
      ). This led to a two-stage model for CAR activation in which (i) translocation into the nucleus was induced by PB-like inducers and (ii) CAR was directly activated by some of the inducers. The translocation was inhibited by okadaic acid, suggesting that phosphatase activity is required for the translocation (
      • Kawamoto T.
      • Sueyoshi T.
      • Zelko I.
      • Moore R.
      • Washburn K.
      • Negishi M.
      ), and activation in the nucleus could be blocked by a Ca2+/CaM-dependent protein kinase inhibitor, suggesting a role for phosphorylation in the activation (
      • Zelko I.
      • Negishi M.
      ).
      The mechanism by which CAR transactivates the PBRU is not clear. In transient transfections, in addition to the NR-1 and NR-2 CAR-binding sites, a nuclear factor 1 site between and sequences flanking these NR sites are required for maximal PB induction (
      • Honkakoski P.
      • Moore R.
      • Washburn K.A.
      • Negishi M.
      ,
      • Honkakoski P.
      • Negishi M.
      ,
      • Stoltz C.
      • Vachon M.-H.
      • Trottier E.
      • Dubois S.
      • Paquet Y.
      • Anderson A.
      ,
      • Liu S.
      • Park Y.
      • Rivera-Rivera I., Li, H.
      • Kemper B.
      ). Like other nuclear receptors, CAR transactivation probably involves coactivator proteins. The p160 coactivator SRC-1 has been shown to bind to CAR both biochemically and in two-hybrid studies, and the binding was decreased by antagonists, androstanes, and increased by the agonist, TCPOBOP (
      • Forman B.M.
      • Tzameli I.
      • Choi H.-S.
      • Chen J.
      • Simha D.
      • Seol W.
      • Evans R.M.
      • Moore D.D.
      ,
      • Tzameli I.
      • Pissios P.
      • Schuetz E.G.
      • Moore D.D.
      ). In primary cultures of hepatocytes, SRC-1 expression alone increased transactivation of the PBRU but not a synthetic enhancer with two of the CAR NR-1 sites about 3-fold in untreated cells and similarly increased transcription 2–3-fold in cells expressing exogenous CAR (
      • Muangmoonchai R.
      • Smirlis D.
      • Wong S.C.
      • Edwards M.
      • Phillips I.R.
      • Shephard E.A.
      ). These results suggest that p160 coactivators interact with and enhance transactivation by CAR, but the relatively small increases in transactivation mediated by overexpressed SRC-1 and the assay of activity in cultured hepatocytes in which the relative concentrations of regulatory factors may differ from hepatocytes in vivofall short of establishing a role for these coactivators in PB induction.
      SRC-1 is a member of a family of related p160 coactivators that includes SRC-1, TIF2/GRIP1, and RAC3/ACTR/pCIP/AIB-1 (
      • Leo C.
      • Chen J.D.
      ). GRIP1 has been shown to coactivate hepatic nuclear receptors, for example hepatic nuclear factor 4 (
      • Dong Y.
      • McGurie J.
      • Okret S.
      • Poellinger L.
      • Makino I.
      • Gustafsson J.
      ,
      • Estabrook R.W.
      • Hilderbrandt A.G.
      • Baron J.
      • Netter K.J.
      • Leibman K.
      ), and thus is a potential coactivator for CAR in the liver. We now show that GRIP1 interacts with CAR and with DNA-bound CAR·RXR and that the binding is modulated by ligands. GRIP1 modestly enhances CAR-mediated activation in continuously cultured cells. Remarkably, in untreated mice, exogenous expression of GRIP1 in hepatocytes transfected in vivoincreases transactivation of the PBRU more than expression of CAR does, and coexpression with CAR results in a dramatic synergistic activation equal to that resulting from PB treatment. In PB-treated animals, exogenous expression of GRIP1 also results in a 2-fold increase in transactivation, whereas CAR has little effect and a 4-fold increase is observed if both exogenous CAR and GRIP are expressed.

      DISCUSSION

      Previous studies have implicated p160 coactivators in the transactivation mediated by CAR, but these studies rested on showing interactions of SRC-1 with CAR alone (
      • Forman B.M.
      • Tzameli I.
      • Choi H.-S.
      • Chen J.
      • Simha D.
      • Seol W.
      • Evans R.M.
      • Moore D.D.
      ,
      • Tzameli I.
      • Pissios P.
      • Schuetz E.G.
      • Moore D.D.
      ) and modest increases in CAR transactivation resulting from overexpression of SRC-1 in cultured cells (
      • Muangmoonchai R.
      • Smirlis D.
      • Wong S.C.
      • Edwards M.
      • Phillips I.R.
      • Shephard E.A.
      ,
      • Zelko I.
      • Sueyoshi T.
      • Kawamoto T.
      • Moore R.
      • Negishi M.
      ). The present studies confirm the interaction of CAR with a p160 coactivator, GRIP1, and further show that GRIP1 interacts with CAR·RXR heterodimers bound to DNA, which is a more functional form of these nuclear receptors. CAR-mediated transactivation of either the PBRU (data not shown) or four copies of the CYP2B1 NR-1 was enhanced 2–3-fold by expression of GRIP1 in cultured cells. These results are similar to those obtained for the PBRU or βRARE sites when SRC-1 was coexpressed with CAR in primary cultures of hepatocytes or CV-1 cells, respectively (
      • Muangmoonchai R.
      • Smirlis D.
      • Wong S.C.
      • Edwards M.
      • Phillips I.R.
      • Shephard E.A.
      ,
      • Forman B.M.
      • Tzameli I.
      • Choi H.-S.
      • Chen J.
      • Simha D.
      • Seol W.
      • Evans R.M.
      • Moore D.D.
      ), although transactivation of 2 NR-1 sites was not increased by SRC-1 in primary hepatocytes in contrast to the present results with four copies of the NR-1. Although CAR transactivation in cultured cells was only modestly enhanced by GRIP1, exogenous expression of GRIP1 in vivo in untreated mice increased transactivation by 15-fold and increased transactivation by 50-fold in cells exogenously expressing CAR. In PB-treated animals, exogenous expression of GRIP1 enhanced CAR transactivation about 2-fold. The dramatic 50-fold increase in CAR transactivation mediated by GRIP1 expression in vivo in the untreated animals, compared with 2–3-fold increases in cell culture, provides strong additional evidence for the role of p160 coactivators in PB induction of CYP2B genes. GRIP1 has been shown to activate hepatic nuclear receptors, and either the protein or mRNA was reported to be present in human or mouse liver (
      • Gervois P., Vu-
      • Dac N.
      • Kleemann R.
      • Kockx M.
      • Dubois G.
      • Laine B.
      • Kosykh V.
      • Fruchart J.C.
      • Kooistra T.
      • Staels B.
      ,
      • Hong H.
      • Kohli K.
      • Garbedian M.J.
      • Stallcup M.R.
      ,
      • Voegel J.J.
      • Heine M.J.
      • Zechel C.
      • Chambon P.
      • Gronemeyer H.
      ), but it was recently reported that GRIP1 was not detectable in hepatic parenchymal cells using immunocytochemical techniques (
      • Puustinen R.
      • Sarvilinna N.
      • Manninen T.
      • Tuohimaa P.
      • Ylikomi T.
      ). Thus, either SRC-1 or AIB1/p/CIP/SRC-3, the latter of which is predominantly expressed inXenopus liver (
      • Kim H.-J.
      • Lee S.-K., Na, S.-Y.
      • Choi H.-S.
      • Lee J.W.
      ), may function as the p160 form interacting with CAR in the liver.
      The binding of GRIP1 to GST-CAR in vitro was increased by the agonist TCPOBOP and decreased by the antagonist androstenol, which is consistent with earlier studies in which ligands modulated binding of SRC-1 to CAR (
      • Forman B.M.
      • Tzameli I.
      • Choi H.-S.
      • Chen J.
      • Simha D.
      • Seol W.
      • Evans R.M.
      • Moore D.D.
      ,
      • Tzameli I.
      • Pissios P.
      • Schuetz E.G.
      • Moore D.D.
      ). Interesting differences were observed in the binding between CAR and different fragments of GRIP1 containing the central receptor interacting sites and either the N-terminal portion or the C-terminal portion of molecule. Both types of fragments bound to CAR alone, but binding was modulated by ligand only for the C-terminal fragment. In gel shift assays, little binding of GRIP1 to CAR·RXR·DNA complexes was observed with the N-terminal fragment, but binding was observed with the C-terminal fragment even if only one of the three LXXLL motifs in the nuclear interaction domain was present. This binding was increased by the CAR agonist TCPOBOP and decreased by the antagonist androstenol. The role of LXXLL in binding of GRIP1 to CAR has not been established, but there appears to be little specificity for individual LXXLL motifs because mutation individually of each of the three LXXLL motifs in the nuclear receptor interaction domain did not alter the interaction of CAR and the related p160 coactivator from Xenopus, xSRC-3 (
      • Kim H.-J.
      • Lee S.-K., Na, S.-Y.
      • Choi H.-S.
      • Lee J.W.
      ). These results suggest that effects on the binding of GRIP1 to CAR by ligands is mediated through the C-terminal portion of the molecule, analogous to ligand-dependent nuclear receptors, such as the steroid hormone receptors, and that the C-terminal portion is required for stable binding of GRIP1 to CAR under the conditions of the gel shift assay.
      It has been reported that exogenous expression of CAR inhibited PB induction of CYP2B1 in primary cultures of hepatocytes and that changing the PBRU NR-1 site to a βRARE site, which still binds CAR, eliminated PB induction (
      • Paquet Y.
      • Trottier E.
      • Beaudet M.-J.
      • Anderson A.
      ). These results led to the proposal that CAR was not involved in PB induction of CYP2B genes. An alternate explanation of these results is that CAR is saturating in the nucleus after PB treatment, so that expression of additional CAR has little effect and may be inhibitory. The present result that exogenous expression of CAR in PB-treated animals does not increase transactivation unless GRIP1 is expressed exogenously as well provides support for this alternate explanation and suggests that the p160 coactivator is limiting relative to CAR in the PB-treated hepatocyte. The loss of PB induction in transgenic mice with disrupted CAR genes (
      • Wei P.
      • Zhang J.
      • Egan-Hafley M.
      • Liang S.
      • Moore D.D.
      ) and other studies showing that exogenous CAR expression increased transactivation of the PBRU in PB-treated primary cultures of hepatocytes or hepatocytes transfected in situ by bolistic particles (
      • Muangmoonchai R.
      • Smirlis D.
      • Wong S.C.
      • Edwards M.
      • Phillips I.R.
      • Shephard E.A.
      ) also support a role for CAR in PB induction. Possible explanations for the loss of PB induction observed with the conversion the PBRU NR-1 site to a βRARE site (
      • Paquet Y.
      • Trottier E.
      • Beaudet M.-J.
      • Anderson A.
      ) are that the conformation of CAR·RXR may be different when bound to the βRARE site (
      • Wood J.R.
      • Likhite V.S.
      • Loven M.A.
      • Nardulli A.M.
      ) or the alignment of CAR·RXR with other proteins binding to the PBRU may be changed (
      • Kim T.K.
      • Maniatis T.
      ), resulting in a loss of transactivation.
      The most surprising result in this study was the dramatic synergistic effects of exogenous CAR and GRIP1 expression in untreated animals resulting in a 150-fold increase in transactivation. The basis for the synergistic effect is most likely due to two effects of the expression of exogenous GRIP1, translocation of CAR to the nucleus, and direct activation of CAR by GRIP1. Exogenous expression of GRIP1 resulted in nuclear localization of GFP-CAR in essentially all of the transfected hepatocytes, although the extent of translocation was heterogenous and less complete than that observed in PB-treated cells. Direct activation of CAR by GRIP1 is about 2-fold based on the effects of GRIP1 in cultured cells and in PB-treated mice, so that most of the synergistic 150-fold effect in untreated animals is the result of translocation of CAR to the nucleus. Because in cultured cells, CAR is always present in the nucleus, the difference in localization of CAR explains most of the dramatic difference in magnitude of the GRIP1 effect in cultured cells and in vivo. In addition, the PBRU is a complex enhancer with DNA-binding proteins other than CAR contributing to the PB response, (
      • Honkakoski P.
      • Moore R.
      • Washburn K.A.
      • Negishi M.
      ,
      • Honkakoski P.
      • Negishi M.
      ,
      • Stoltz C.
      • Vachon M.-H.
      • Trottier E.
      • Dubois S.
      • Paquet Y.
      • Anderson A.
      ,
      • Liu S.
      • Park Y.
      • Rivera-Rivera I., Li, H.
      • Kemper B.
      ) and coactivators or cosuppressors other than the p160 coactivators may be also recruited to the PBRU. The differences in concentration of these factors in cultured cells and in vivomay contribute to the differences observed for the effects of GRIP1 expression in these two systems.
      These studies raise the possibility that PB activation of GRIP1 might contribute to the translocation of CAR to the nucleus after PB treatment. Although the action of PB is poorly understood, the phosphatase inhibitor, okadaic acid, inhibits CAR nuclear translocation (
      • Kawamoto T.
      • Sueyoshi T.
      • Zelko I.
      • Moore R.
      • Washburn K.
      • Negishi M.
      ). The target of the phosphatase, presumed to be CAR, has not been directly identified. Precedents exist for modulation of GRIP1 activity by phosphorylation (
      • Lopez G.N.
      • Turck C.W.
      • Schaufele F.
      • Stallcup M.R.
      • Kushner P.J.
      ) and for translocation of regulatory proteins by coregulators, for example translocation of histone deacetylase-4 by SMRT (silencing mediator forretinoic acid receptor and thyroid hormone receptor) (
      • Wu X., Li, H.
      • Park E.J.
      • Chen J.D.
      ), so that it is possible that dephosphorylation of a p160 coactivator could contribute to the PB response. An activated GRIP1 could mediate translocation of CAR either by interacting with cytoplasmic CAR and inducing nuclear translocation or by interacting with nuclear CAR and enhancing of nuclear retention of CAR. The latter mechanism would be possible if CAR is continuously shuttling between the nucleus and cytoplasm even in untreated animals as has been proposed for nuclear receptors (
      • Freeman B.C.
      • Yamamoto K.R.
      ). Any GRIP effect on CAR nuclear translocation would have to be independent of its effect on activation of CAR because CAR with the C-terminal transactivation domain inactivated by deletion is still translocated to the nucleus (
      • Zelko I.
      • Sueyoshi T.
      • Kawamoto T.
      • Moore R.
      • Negishi M.
      ). Further studies will be required to establish the mechanism by which p160 coactivators induce CAR nuclear translocation and the role of this effect in PB induction of CYP genes.

      Acknowledgments

      We thank M. R. Stallcup and R. Evans for supplying plasmids and Jun Xia for assistance in collecting and analyzing images of GFP expressing cells.

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