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J. Biol. Chem., Vol. 275, Issue 43, 33201-33204, October 27, 2000

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ACCELERATED PUBLICATION
Ligand type-specific Interactions of Peroxisome Proliferator-activated Receptor  with Transcriptional Coactivators^*

Yasuo Kodera, Ken-ichi Takeyama^§, Akiko Murayama, Miyuki Suzawa^§, Yoshikazu Masuhiro^§, and Shigeaki Kato^§¶

From the  Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan and the ^§ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan

Received for publication, August 2, 2000, and in revised form, August 11, 2000

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

The nuclear peroxisome proliferator-activated receptor  (PPAR) is a member of the nuclear receptor superfamily and acts as a ligand-dependent transcription factor mediating adipocyte differentiation, cell proliferation and inflammatory processes, and modulation of insulin sensitivity. Members of the 160-kDa protein (SRC-1/TIF2/AIB-1) family of coactivators, CBP/p300 and TRAP220/DRIP205, are shown to interact directly with PPAR and potentiate nuclear receptor transactivation function in a ligand-dependent fashion. Because PPAR ligands exert partially overlapping but distinct subsets of biological action through PPAR binding, we wished to examine whether interactions between PPAR and known coactivators were induced to the same extent by different classes of PPAR ligand. The natural ligand 15-deoxy-12,14-prostaglandin J₂ induced PPAR interactions with all coactivators tested (SRC-1, TIF2, AIB-1, p300, TRAP220/DRIP205) in yeast and mammalian two-hybrid assays, as well as in a glutathione S-transferase pull-down assay. However, under the same conditions troglitazone, a synthetic PPAR ligand that acts as an antidiabetic agent, did not induce PPAR interactions with any of the coactivators. Our findings suggest that ligand binding may alter PPAR structure in a ligand type-specific way, resulting in distinct PPAR-coactivator interactions.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Peroxisome proliferator-activated receptor  (PPAR),¹ a member of the nuclear hormone receptor superfamily, acts as a ligand-inducible transcription factor (1, 2). PPAR forms a heterodimer complex with one of the three retinoid X receptor (RXR) proteins, which then binds to PPAR-responsive elements (PPRE) within the promoters of PPAR target genes (3, 4). It is thought that the ligand binding domain (LBD) mediates the ligand-dependent transactivation function of PPAR, although two transactivation domains, at the N-terminal (AF-1) and C-terminal ends (AF-2), are present in most nuclear receptors. Ligand-induced transactivation is achieved by the nuclear receptor recruiting one of several types of nuclear receptor coactivator complex. One class of coactivator complex includes three SRC-1 family members (5), CBP/p300 (6), and SRA (7), as well as other proteins (8, 9). The SRC-1 family members (SRC-1 (p160/NCoA-1) (10), TIF2 (GRIP-2) (11), and AIB1 (p/CIP/ACTR) (12)) interact with the AF-2 nuclear receptors. This interaction is highly ligand-dependent through direct binding to the minimal activation domain of AF-2 (AF-2 AD), mapped to the C-terminal -helix 12 (H12) in the LBD (13). CBP/p300 serves as an essential coactivator not only for nuclear receptors but also for other classes of transcription regulatory factor (14) and, like the SRC-1 family members, possesses histone acetyltransferase activity (15). Another coactivator complex, TRAP/DRIP, contains at least 12 components, one of which exhibits direct and ligand-dependent interaction with H12 in the LBD (TRAP220/DRIP205/PBP) (16, 17).

Reflecting on the role of the PPAR function in many biological events, a variety of endogenous and synthetic ligands have been reported to activate the transactivation function of PPAR. Of the natural ligands for PPAR, prostaglandin derivative 15-deoxy-12,14 prostaglandin J₂ (15d-PGJ2) and 9- or 13-hydoxyoctadienoic acid (9-HODE or 13-HODE) are known to mediate potent adipogenesis and anti-inflammatory effects. Several synthetic thiazolidinedione derivatives, such as troglitazone, BRL49653, and pioglitazone, have been developed for anti-hyperglycemic activity in vivo (18-21). In this study, we hypothesized that the ligand type-specific effects mediated by PPAR are exerted through ligand type-specific structures on PPAR, allowing different coactivator associations. This conjecture of ligand type-specific structures on PPAR is supported by ER LBD crystallographic findings showing that ligand binding altered LBD structure with distinct and ligand type-specific shifts in the H12 angle (22). To examine our hypothesis, we studied the interactions between PPAR bound to distinct ligands with known nuclear receptor coactivators. Although both ligands used were equally potent in the transactivation function of PPAR, direct interactions of PPAR with SRC-1, TIF2, AIB-1, p300, and TRAP220 were observed when 15d-PGJ2 was bound but not when troglitazone was bound. Consistent with these coactivator-specific interactions, the transactivation function of troglitazone-bound PPAR was not potentiated by coactivator overexpression. Thus, the present findings suggest that PPAR structure is altered in a ligand-specific way, resulting in distinct interactions between PPAR and coactivators.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Plasmid Construction-- cDNA encoding human PPAR2 obtained from a human liver cDNA library (23) was subcloned into the pGEX (Amersham Pharmacia Biotech) and pSG5 (Stratagene) expression vectors. The pVP16(GAL4-AD)-PPAR2(DEF) fusion plasmid was constructed by inserting human PPAR2 ligand-binding regions (encoding amino acids 183-505) into the pVP16 expression vector (CLONTECH). Each coactivator cDNA was inserted into the pM vector (CLONTECH) that included a GAL4 transactivation domain. The following plasmids constructed in a mammalian expression vector (Invitrogen) have been described previously (24): pcDNA3-human SRC-1 (hSRC-1), pcDNA3- hTIF2, pcDNA3-hAIB-1, and pcDNA3-hp300. The pcDNA3-TRAP220 expression vector was created by isolating TRAP220 cDNA from a human brain cDNA library. Mouse RXR cDNA expression vector pGEX-mRXR, a gift from P. Chambon, was subcloned into the pSG5 vector (25).

Mammalian Two-hybrid Assay-- COS-1 cells were maintained in Dulbecco's modified Eagle's medium without phenol red, supplemented with 5% fetal calf serum stripped with dextran-coated charcoal. Cells were transfected by calcium phosphate coprecipitation as described previously (24). Reporter plasmid (1 µg) containing GAL4-UAS (17-mer ×2 (-globin promoter) CAT) was cotransfected with 0.2 µg of pVP-PPAR2(DEF) plus 0.2 µg of either pM-SRC-1, pM-TIF2, pM-AIB-1, pM-p300 or pM-TRAP220. As a reference plasmid for normalization, 2 µg of pCH110 plasmid was used (Amersham Pharmacia Biotech). Bluescribe M13⁺ (Stratagene) was used as the carrier to adjust the total amount of DNA to 5 µg. 15d-PGJ2 or troglitazone (0.1-100 µM) was added to the medium 12 h after transfection and every 8 h thereafter at each exchange of medium. After 48 h, CAT activity was assayed, and transfection efficiency was normalized to -galactosidase activity as described previously (26).

GST Pull-down Assays-- Full-length human PPAR2 cDNA was expressed as a GST fusion protein (GST-PPAR2) in Escherichia coli strain HB101 as described (24). The expression of a protein of the predicted size was then monitored by SDS-PAGE. For GST pull-down assays, bacterially expressed GST or GST-PPAR2 was bound to glutathione-Sepharose 4B beads (Amersham Pharmacia Biotech). SRC-1, TIF2, AIB-1, p300, and TRAP220 cDNA cloned into pcDNA3 were used to generate [³⁵S]methionine (Amersham Pharmacia Biotech)-labeled proteins using a TNT-coupled in vitro translation system (Promega). The ³⁵S-labeled SRC-1, TIF2, AIB-1, p300, and TRAP220 proteins were incubated with beads containing either GST or GST-PPAR2 in the absence or presence of either 0.1 µM 15deoxy-^12,14prostaglandin J₂ (15d-PGJ2), 9-hydoxyoctadienoic acid (9-HODE), or troglitazone in NET-N buffer (0.5% Nonidet P-40, 20 mM Tris-HCl, pH 7.5, 200 mM NaCl, 1 mM EDTA) with 1 mM phenylmethylsulfonyl fluoride. After a 3-h incubation, beads were washed with NET-N buffer to remove free protein. Bound proteins were extracted into loading buffer, separated by 7.5% SDS-PAGE, and visualized by autoradiography. Polyacrylamide gels were lightly stained with Coomassie Brilliant Blue to verify loading of equal quantities of fusion proteins prior to drying and autoradiography.

Electrophoretic Mobility Shift Assay-- The interaction of TIF2 with ligand-bound PPAR2-RXR was determined by electrophoretic mobility shift assays with DNA probes as described (24). GST-PPAR2, GST-RXR, and GST-TIF2 were expressed in E. coli as GST fusion proteins and purified by digestion with thrombin following affinity column chromatography. Digested samples were applied to Sephadex G-100 to further purify the PPAR2, RXR, and TIF2 proteins with protein purity and quantity monitored by SDS-PAGE. In a typical assay, 10 ng of recombinant PPAR2 and/or RXR protein with or without 10 ng of TIF2 protein in the presence or absence of 10⁷ M 15d-PGJ2 or troglitazone were incubated for 30 min on ice in a binding buffer (5 mM Tris, pH 8.0, 40 mM KCl, 6% glycerol, 1 mM dithiothreitol, 0.05% Nonidet P-40), 2 µg of poly(dI·dC), 0.1 µg of denatured salmon sperm DNA, and 10 µg of bovine serum albumin in a final volume of 20 µl. Double-stranded consensus mouse acyl-CoA oxidase-PPRE (PPRE; 5'-GTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAGT-3') DNA fragments (3) were end-labeled using [-³²P]ATP and T4 polynucleotide kinase and used as probe. PPRE DNA fragments were added to the binding mixtures, and the mixtures was incubated for 20 min at room temperature. The entire reaction mixture (20 µl) was loaded onto 4.5% polyacrylamide gels in 0.5× Tris-acetate-EDTA buffer and electrophoresed at 4 °C. The gels were dried on filter paper and exposed to x-ray film.

Transactivation Assays-- COS-1 cells were maintained as described above for the mammalian two-hybrid system. The following plasmids were used for transfection: respective reporter plasmid (1 µg) containing the pGL-GAL4-UAS (17-mer × 2--globin promoter-luciferase) cotransfected with 0.1 µg of pM(GAL4-DBD)-PPAR (DEF) or pM-PPAR (DEF-AF-2) with or without 1 µg of SRC-1, TIF2, or TRAP220 expression vector. As a reference plasmid for normalization, 10 ng of pRL-CMV plasmid (Promega) was used. Bluescribe M13⁺ (Stratagene) was used as the carrier to adjust the total amount of DNA to 3 µg. 1 µM 15d-PGJ2 or troglitazone was added to the medium 12 h after transfection and every 8 h thereafter at each exchange of medium. After 48 h, firefly luciferase activity (from GAL4-UAS) was used to measure transfection efficiency by Renilla luciferase activity (from pRL-CMV) as described previously (27).

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Ligand Type-specific Interactions of PPAR with Coactivators in the Mammalian Two-hybrid System and GST Pull-down Assay-- We first tested for ligand-induced and dose-dependent interactions of PPAR using two distinct coactivator classes in a mammalian two-hybrid system. For this assay, the LBD of PPAR containing AF-2 was fused to the VP16 domain in the pVP vector (pVP-PPAR (DEF)), and several coactivators (SRC-1, TIF2, AIB-1, p300, and TRAP220/DRIP205) (24) fused to the GAL4 activation domain in the pM vector. The natural ligand 15d-PGJ2 (0.1 µM) induced PPAR interactions with SRC-1, TIF2, AIB-1, p300, and TRAP220 (Fig. 1A); however, no ligand-dependent interaction with coactivators was detected after 9-HODE binding. Troglitazone (1 µM), a synthetic PPAR ligand, induced no PPAR interactions with any of the coactivators tested, and showed only weak interaction between PPAR and SRC-1 or p300 at 10 µM. It is notable that both 15d-PGJ2 (0.1 µM) and troglitazone were equally potent in ligand-induced transactivation by PPAR (Fig. 3). This ligand type-specific interaction between PPAR and coactivators was also observed using a yeast two-hybrid system (data not shown).

View larger version (19K): [in this window] [in a new window]   Fig. 1.   Ligand type-specific interactions of PPAR with coactivators in the mammalian two-hybrid system and GST-pull down assay. Different interactions between PPAR and coactivators were induced by natural ligands and troglitazone using the mammalian two-hybrid system (A). COS-1 cells were transiently transfected with a reporter plasmid (17M2-G-CAT) and pVP(VP16)-PPAR(DEF) with or without pM(Gal4-DBD)-SRC-1, pM-TIF2, pM-AIB-1, pM-p300, or pM-TRAP220 expression plasmids. Twelve hours after transfection, the transfected cells were treated with the indicated analogs at concentrations of 10-0.1 µM and harvested for luciferase assay at 48 h post-transfection. Results are presented as the mean ± S.D. of six independent experiments. Troglitazone does not induce interactions between GST-PPAR and the SRC-1 family, p300, or TRAP220 proteins in the GST pull-down assay (B). GST-PPAR was expressed in E. coli and immobilized on glutathione-Sepharose beads. In vitro translated SRC-1, TIF2, AIB-1, p300, and TRAP220 labeled with [35S]methionine were incubated with the beads in the absence of added ligand () or in the presence of 15d-PGJ2, 9-HODE, or troglitazone at a concentration of 1 µM. As a positive control, the 1/10 amount of labeled SRC-1, TIF2, AIB-1, p300, and TRAP220 proteins are shown in the first lane. Representative GST pull-down assays and graphs corresponding to the means ± S.D. for triplicate independent experiments are shown.

We then determined whether ligand-dependent interaction of PPAR with coactivators was ligand type-specific in vitro using a GST pull-down assay. [³⁵S]Methionine-labeled SRC-1, TIF2, AIB-1, p300, and TRAP220 were applied to glutathione-beads with GST-fused PPAR protein in the presence and absence of ligand. Consistent with the results from the mammalian and yeast two-hybrid systems, the 15d-PGJ2-bound PPAR physically interacted with all coactivators (Fig. 1B), whereas troglitazone failed to induce PPAR-coactivator interaction. A GST did not bind to all of the coactivators in the presence of ligands (data not shown).

Troglitazone Binding Is Unable to Recruit TIF2 to the PPAR-RXR Heterodimer upon PPRE Binding-- We next tested whether troglitazone binding induced coactivator interactions with a DNA-bound PPAR/RXR heterodimer. An electrophoretic mobility shift assay with a well characterized consensus PPRE from the acyl-coenzyme A oxidase gene (acyl-CoA) promoter (3) was used. As shown in Fig. 2, despite the absence of 15d-PGJ2 or the RXR-specific ligand (LG268), PPAR/RXR heterodimer DNA binding was observed, whereas binding of the single receptors was not observed (lane 4). TIF2 recruitment induced the formation of a larger complex, observed as a slow migrating band produced by the binding of 15d-PGJ or LG268 to PPAR/RXR (lanes 9 and 11). However, TIF2 recruitment was not induced by troglitazone binding (lane 10).

View larger version (61K): [in this window] [in a new window]   Fig. 2.   Troglitazone binding is unable to recruit TIF2 to the PPAR-RXR heterodimer bound to PPRE. Purified PPAR, RXR, and the receptor-interaction domain of TIF2 fused to GST were incubated with 32P-labeled PPRE in a binding mixture in the presence or absence of 1 µM 15d-PGJ2, troglitazone, and LG268 for an electrophoretic mobility shift assay as described under "Experimental Procedures." The PPAR/RXR heterodimer and PPAR/RXR-TIF2 complex are indicated by arrows.

Ligand-specific Potentiation of PPAR Transactivation Function by Coactivators-- The observations that PPAR interactions with SRC-1 family members, p300, and TRAP220 proteins were ligand type-specific, suggesting that the transactivation function of ligand-bound PPAR was differentially potentiated by these coactivators. A transient expression assay was performed in COS-1 cells using pM (GAL4-DBD)-PPAR (DEF), pM-PPAR(DEF-AF-2), and a reporter plasmid (GAL4-UAS-luciferase) containing the luciferase gene along with consensus GAL4 upstream activating sequence. As shown in Fig. 3, the transactivation function of PPAR induced by troglitazone (lane 4) was comparable with that induced by 15d-PGJ2 (lane 2). 9-HODE was unable to induce significant transactivation even with wild-type PPAR (lane 3). Moreover, the transactivation function of PPAR induced by the two ligands was disrupted in the same way when the AF-2 AD core (H12) sequence was deleted (PPAR(DEF-AF-2)) (lanes 6 and 8). SRC-1 and TIF2 significantly enhanced the transactivation function of PPAR induced by 15d-PGJ2 (lanes 10, 13), and a potentiation by TRAP220 was also seen but was not statistically significant (lane16). However, the troglitazone-induced transactivation function of PPAR was not potentiated by these coactivators (lanes 11, 14, and 17). Thus, although 15d-PGJ2 appears to alter PPAR LBD structure to allow coactivator recruitment, troglitazone-bound LBD may be modulated in some other way.

View larger version (17K): [in this window] [in a new window]   Fig. 3.   Ligand-specific potentiation of PPAR transactivation function by coactivators. COS-1 cells were transfected with a reporter plasmid (17M8-TATA-Luc), pM(GAL4-DBD)-PPAR LBD, or pM(GAL4-DBD)-PPAR-LBD(AF2) with or without SRC-1, TIF2, or TRAP220 expression vectors in the presence or absence of 1 µM 15d-PGJ2 or troglitazone and harvested for luciferase assay 48 h post-transfection as described under "Experimental Procedures." The results are presented as the mean ± S.D. of six independent experiments.

PPAR-mediated signaling is involved in a variety of biological events, such as adipocyte differentiation, cell proliferation, and inflammatory processes (2). To modulate particular PPAR-mediated events, synthetic PPAR ligands have been developed in addition to the identification of endogenous ligands 15d-PGJ2 and 9-HODE. Interestingly, the biological actions mediated by PPAR were reported to differ according to the ligand used (28). These observations led us to examine the molecular mechanism underlying the ligand-specific actions of the PPAR ligands. Structural analyses by crystallography revealed that the LBD structures of many nuclear receptors were altered in a ligand type-specific way, particularly at helix 12 (29, 30). As the alteration of the helix 12 angle upon ligand binding to the nuclear receptor LBD is now considered essential for coactivator recruitment, we decided to examine the interactions between coactivators and PPAR bound to distinct classes of PPAR ligands. Both 15d-PGJ2 and troglitazone at the same concentration (1 µM) were equally potent in the induction of PPAR transactivation function, whereas the other endogenous ligand tested, 9-HODE, was unable to activate PPAR transactivation. Ligand-dependent interactions of PPAR with the tested coactivators were observed using 15d-PGJ2 by both in vivo and in vitro assays. However, troglitazone binding to PPAR failed to induce coactivator interactions in these assays, indicating that the mode of coactivator interaction with PPAR was ligand type-specific. These findings imply that troglitazone-bound PPAR may recruit components other than TRAP220/DRIP205 in the DRIP/TRAP coactivator complex, or proteins other than the 160-kDa family proteins and CBP/p300 in the SRC-1 family-type coactivator complex to form transcription initiation complexes. An alternative possibility is that an unknown coactivator complex may be recruited to troglitazone-bound PPAR. In this respect, it would be interesting to examine whether troglitazone could induce PPAR interaction with PGC-1 and PGC-2, which are also reported to act as PPAR coactivators (31, 32). Nevertheless, as ligand-induced coactivator interactions with PPAR appear to be distinct between 15d-PGJ2 and troglitazone, the overall structure of PPAR and coactivator complexes may be different according to the ligands involved, resulting in the activation of a particular set of target gene promoters that exert different biological actions.

	ACKNOWLEDGEMENTS

We thank T. Asahina, H. Fuse, S. Kitanaka, D Matsui, F Otake, I. Takada, and J. Yanagisawa for helpful technical advice, Sankyo Pharmaceuticals for supplying troglitazone, and Prof. P. Chambon for the generous gift of mouse RXR cDNA.

	FOOTNOTES

^* This work was supported in part by a grant-in-aid for priority areas from the Ministry of Education, Science, Sports and Culture of Japan (to S. K.).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.

^¶ To whom correspondence should be addressed: Inst. of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan. Tel.: 81-3-5841-8478; Fax: 81-3-5841-8477; E-mail: uskato@mail.ecc.u-tokyo.ac.jp.

Published, JBC Papers in Press, August 15, 2000, DOI 10.1074/jbc.C000517200

	ABBREVIATIONS

The abbreviations used are: PPAR, peroxisome proliferator-activated receptor ; RXR, retinoid X receptor; LBD, ligand binding domain; AF-2, activation function-2; 15d-PGJ2, 15deoxy-^12,14prostaglandin J2; 9-HODE, 9-hydroxyoctadienoic acid; SRC-1, steroid receptor coactivator-1; TIF2, transcriptional intermediate factor 2; AIB-1, amplified in breast cancer-1; CBP, CREB-binding protein; SRA, steroid receptor RNA coactivator; TRAP220, thyroid hormone-associated protein 220; PGC-1, PPAR  coactivator-1; PPRE, peroxisome proliferator-activated response element; acyl-CoA, acyl-coenzyme A oxidase; PAGE, polyacrylamide gel electrophoresis; AD, activation domain; CAT, chloramphenicol acetyltransferase; GST, glutathione S-transferase; UAS, upstream activating sequence.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

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