9-cis-Retinoic Acid Up-regulates Expression of Transcriptional Coregulator PELP1, a Novel Coactivator of the Retinoid X Receptor α Pathway

Retinoid X receptor α (RXRα), functioning as either a homodimer or a heterodimer with peroxisome proliferator receptors, is known to be involved in manifesting antiproliferative effects in cells. Consequently, studies of RXRα functions and its coregulators have been in the focus for therapeutic approaches against cancer. Here we have discovered that 9-cis-retinoic acid (9-cis-RA), a RXRα-specific ligand, up-regulated the expression of transcriptional coregulatory protein PELP1 (proline-, glutamic acid-, and leucine-rich protein 1). PELP1 functioned as a coactivator of RXRα, increasing its transactivation function in response to 9-cis-RA as evident by the retinoid X receptor response element-luciferase assays. PELP1 was found to be a binding partner of RXRα, and the binding interactions were confirmed both in vitro and in vivo. An electrophoretic mobility shift assay showed greater formation and stability of RXRα homodimers on consensus oligonucleotides in PELP1-overexpressing clones in comparison to the pcDNA clones. The presence of PELP1 in these oligonucleotide-bound RXRα homodimers was proved by the supershift of the complex when incubated with PELP1-specific antibody. PELP1-overexpressing stable MCF-7 cells exhibited a significantly higher extent of 9-cis-RA-induced apoptosis than the control pcDNA clones. Silencing of PELP1 expression in parental MCF-7 cells and PELP1-overexpressing clones using PELP1-specific RNA-mediated interference compromised the susceptibility to 9-cis-RA-induced apoptosis. PELP1 could also function as a coactivator of the RXRα-peroxisome proliferator-activated receptor (PPARγ) heterodimer as evident by the peroxisome proliferator-activated receptor response element-luciferase assay in response to both 9-cis-RA and PPARγ-specific ligands. This was reinforced by the higher propensity of PELP1-overexpressing clones to undergo differentiation in response to PPARγ-specific ligands. This study has revealed a novel facet of PELP1 functions and identified it to be an important potentiator of the antiproliferative effects of 9-cis-RA and PPARγ-specific ligands. Retinoid X receptor α (RXRα), functioning as either a homodimer or a heterodimer with peroxisome proliferator receptors, is known to be involved in manifesting antiproliferative effects in cells. Consequently, studies of RXRα functions and its coregulators have been in the focus for therapeutic approaches against cancer. Here we have discovered that 9-cis-retinoic acid (9-cis-RA), a RXRα-specific ligand, up-regulated the expression of transcriptional coregulatory protein PELP1 (proline-, glutamic acid-, and leucine-rich protein 1). PELP1 functioned as a coactivator of RXRα, increasing its transactivation function in response to 9-cis-RA as evident by the retinoid X receptor response element-luciferase assays. PELP1 was found to be a binding partner of RXRα, and the binding interactions were confirmed both in vitro and in vivo. An electrophoretic mobility shift assay showed greater formation and stability of RXRα homodimers on consensus oligonucleotides in PELP1-overexpressing clones in comparison to the pcDNA clones. The presence of PELP1 in these oligonucleotide-bound RXRα homodimers was proved by the supershift of the complex when incubated with PELP1-specific antibody. PELP1-overexpressing stable MCF-7 cells exhibited a significantly higher extent of 9-cis-RA-induced apoptosis than the control pcDNA clones. Silencing of PELP1 expression in parental MCF-7 cells and PELP1-overexpressing clones using PELP1-specific RNA-mediated interference compromised the susceptibility to 9-cis-RA-induced apoptosis. PELP1 could also function as a coactivator of the RXRα-peroxisome proliferator-activated receptor (PPARγ) heterodimer as evident by the peroxisome proliferator-activated receptor response element-luciferase assay in response to both 9-cis-RA and PPARγ-specific ligands. This was reinforced by the higher propensity of PELP1-overexpressing clones to undergo differentiation in response to PPARγ-specific ligands. This study has revealed a novel facet of PELP1 functions and identified it to be an important potentiator of the antiproliferative effects of 9-cis-RA and PPARγ-specific ligands. Nuclear receptors (NR) 2The abbreviations used are: NR, nuclear receptor(s); PELP1, proline-, glutamic acid-, and leucine-rich protein 1; RXRα, retinoid X receptor α; PPARγ, peroxisome proliferator-activated receptor γ; 9-cis-RA, 9-cis-retinoic acid; RNAi, RNA-mediated interference; PIC, preinitiation complex; ER, endoplasmic reticulum; CBP, cAMP-response element-binding protein (CREB)-binding protein; GST, glutathione sulfur-transferase; RT, reverse transcription; CRBP II, cellular retinol-binding protein; EMSA, electrophoretic mobility shift assay; WT, wild type; RXRE, retinoid X receptor response element; PPRE, peroxisome proliferator-activated receptor response element. are ligand-activated transcription factors that on binding to small lipophilic signal molecules facilitate gene transcription and regulate diverse vital biological processes such as cell survival, proliferation, differentiation, and apoptosis (1Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schutz G. Umesono K. Blumberg B. Kastner P. Mark M. Chambon P. Evans R.M. Cell. 1995; 83: 835-839Abstract Full Text PDF PubMed Scopus (6164) Google Scholar). On activation, the NR in their homodimeric or heterodimeric complexes with other NR bind to specific DNA sequences referred to as “response elements,” which are present in the regulatory elements of target genes. On DNA binding, the NR orchestrate gene transcription by interacting with the basal transcriptional machinery through bridging factors, referred to broadly as coactivator proteins. One of the potential functions of the coactivator proteins is to directly or indirectly remodel the local chromatin structure through covalent modification of histones (acetylation, phosphorylation, or methylation) resulting in opening of chromatin, greater accessibility of the target gene promoter to transcriptional machinery, and ultimately, gene transcription. Numerous families of coactivators of different NR have been identified. Their mode of interaction with the receptors and the molecular mechanism by which they function has been established. The most well studied coactivators include p300/CBP, p300/CBP-associated factor, and members of the p160 families, which include SRC-1, GRIP1/TIF2/SRC-2, and ACTR/AIB1/RAC3/SRC-3 (for review, see Ref. 2Lonard D.M. O'Malley B.W. Trends Biochem. Sci. 2005; 30: 126-132Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). These coactivators function by facilitating the initial penetration of the chromatin by histone acetylation. Coactivators, which utilize histone methylation for the same purpose like CARM1 and PRMT, have also been identified (3Stallcup M.R. Oncogene. 2001; 20: 3014-3020Crossref PubMed Scopus (156) Google Scholar). In addition to these families, several other coactivator proteins have been identified that function directly at the level of the preinitiation complex (PIC), enhancing its activity. This group includes TATA box-binding protein-associated factors (4Verrijzer C.P. Tjian R. Biochem. Sci. 1996; 21: 338-342Crossref PubMed Scopus (319) Google Scholar), positive cofactors PC1, PC2, PC3, PC5, and PC52 (5Roeder R.G. Cold Spring Harbor Symp. Quant. Biol. 1998; 63: 201-218Crossref PubMed Scopus (145) Google Scholar), and several multiprotein complexes that are related to thyroid hormone receptor-associated protein-mediator complex (6Malik S. Roeder R.G. Trends Biochem. Sci. 2000; 25: 277-283Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) was a recent addition to the family of transcriptional coregulatory proteins and was identified as a novel estrogen receptor (ER) coactivator (7Vadlamudi R.K. Wang R.-A. Mazumdar A. Kim Y. A. R. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). is a protein of that is in glutamic acid and was as has the and in the with and significantly the transcriptional function of that it functions as an PELP1 have the same on receptor and that it be an it has a molecular of showed it was the p160 family of The of p160 proteins such as and are in could with transcriptional like and in which that PELP1 transcription by coactivators such as and PELP1 also with a cell its in an increasing cell S. R.K. Biol. Full Text Full Text PDF Scopus Google Scholar). of cells with was an of PELP1 to the and with the histone of were on estrogen PELP1 also with histones and and transcription by chromatin modification the of S. R. R.K. 2000; Scopus Google Scholar). In PELP1 was confirmed to as an coactivator as a of receptor and of transcription factors protein nuclear and complex response Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The of PELP1 was to its to which in the of histones and and as for histone binding to the the of PELP1, with a in the of histone it was also that PELP1 functions as a coactivator of signal and its transcriptional B. Wang R.-A. R. R.K. 2005; PubMed Scopus Google Scholar). This positive is by the of PELP1 to of of of the protein that PELP1 function as a positive and a of transcription in a transcription and their are of A. are that a vital in the and of by cell differentiation, proliferation, and apoptosis Trends 2001; Full Text Full Text PDF PubMed Scopus Google 2000; PubMed Scopus Google Scholar). their through well studied of receptors acid receptor and retinoid X receptor in of the retinoid receptors have been identified and are referred to as and and is by a gene (1Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schutz G. Umesono K. Blumberg B. Kastner P. Mark M. Chambon P. Evans R.M. Cell. 1995; 83: 835-839Abstract Full Text PDF PubMed Scopus (6164) Google P. 1996; PubMed Scopus Google Scholar). a of NR as they function as members of of NR with also with several other receptors such as thyroid hormone receptors, receptors Umesono K. D.J. Evans R.M. PubMed Scopus Google Scholar), and receptors S. Biochem. PubMed Scopus Google Scholar). The bind with to the retinoid 9-cis-retinoic acid In addition to bind to 9-cis-RA and homodimers that bind to the target DNA sequences and gene transcription D.J. S. C. 1998; PubMed Scopus Google Scholar). In the present we discovered that 9-cis-RA expression of the PELP1 PELP1, in with RXRα and functions as a the transcriptional functions of RXRα homodimer and also of its heterodimer with Consequently, PELP1 the effects of 9-cis-RA and the effects of ligands. and cells were and were in and with for RXRα and were was was and was was used as (7Vadlamudi R.K. Wang R.-A. Mazumdar A. Kim Y. A. R. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). and or were and were The and of and cell were S. R. R.K. 2000; Scopus Google Scholar). These cells were in with and were in cells were with D.J. S. C. 1998; PubMed Scopus Google or Cell. Biol. PubMed Scopus Google using the cells were with or as assay was using the assay was a of The PELP1 promoter were used as S. R.K. PubMed Scopus Google Scholar). vitro transcription and of RXRα was using a 1 of in pcDNA was in the presence of in a of The was to 1 with and An was used for and were by of the to and The were by of and PELP1 on with in vitro RXRα to which binding was proteins were by the for at with the proteins with and by The proteins were by the cells was using and with for which was by the at for The cellular retinol-binding protein were by with specific and used for were and and on were in for were in at for cells were incubated with for at in and incubated with with or The DNA was used for nuclear was using an in with to the of is a of at the same cellular level and of proteins is for and with were a in well and for in the or presence of cells were in and with for at and with for was with by 1 were with for by 1 with was a was using to the and the cell cells were in a cells were with 9-cis-RA cell were by using comparison of the cell of cells to with 9-cis-RA a of the extent of cell cell cells were with 9-cis-RA and with and by cell apoptosis was by using an cells were with 9-cis-RA for with was with consensus The were using and PELP1 promoter of PELP1 has been and with to the transcriptional S. R.K. PubMed Scopus Google Scholar). of the PELP1 promoter for transcription binding elements the K. K. 1995; PubMed Scopus Google showed at RXRα heterodimer binding This to 9-cis-RA, an ligand, PELP1 of MCF-7 cells with 9-cis-RA to of the PELP1 expression with in of as evident by the of MCF-7 cells with 9-cis-RA for and of the cell proteins with PELP1-specific showed a in the level of PELP1 protein when with the control cells with in a of PELP1 was in cells on with 9-cis-RA of cells with 9-cis-RA and an of of PELP1 expression On the other of cells with a protein the 9-cis-RA-induced of PELP1 expression This that the in the level of PELP1 by 9-cis-RA was at the transcriptional the transcription of 9-cis-RA on the PELP1 promoter and the we with PELP1 promoter and its In response to 9-cis-RA a in the with which has the PELP1 was The of PELP1 promoter the of the exhibited than a of activity. This has RXRα binding and binding consensus that be for the of these in 1 that the PELP1 gene is a target of 9-cis-RA PELP1 as a of addition to as a coactivator of PELP1 is a of several transcription factors (7Vadlamudi R.K. Wang R.-A. Mazumdar A. Kim Y. A. R. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google S. R. R.K. 2000; Scopus Google Biol. Full Text Full Text PDF PubMed Scopus Google B. Wang R.-A. R. R.K. 2005; PubMed Scopus Google Scholar). 9-cis-RA PELP1 expression we the of PELP1 in retinoid we the of PELP1 on the assay in MCF-7 cells with of of cells with 9-cis-RA in a of by PELP1 as with a by control that PELP1 as a coactivator of RXRα PELP1 of the RXRα we used MCF-7 cells that showed that 9-cis-RA was a of RXRα transactivation in cells with of PELP1 In addition to chromatin such as the coactivator function of PELP1 also binding and of histone which to DNA the and the basal transcriptional of a of DNA binding factors the of the histone binding of PELP1, we also the assay in MCF-7 cells PELP1 histone protein the acid and of binding to histone in Ref. S. R. R.K. 2000; Scopus Google Scholar). found a in the of to RXRα, as was a of by 9-cis-RA in cells as with a in the of cells These confirmed that PELP1 could function as coactivator of RXRα the of 9-cis-RA in cells. The expression of and PELP1 in the stable clones has been The expression of of RXRα and proteins in and cells was by the This that the of in cells was to of a PELP1 and to of the of the RXRα the of the of PELP1 as RXRα was in the stable clones for the expression of CRBP II, an RXRα target In response to 9-cis-RA the expression of CRBP in clones was higher when with the pcDNA clones which important of the of the RXRα transactivation function by PELP1 with PELP1 is a coactivator of RXRα, we PELP1 with the PELP1 and RXRα, that the acid of PELP1, which has of the NR in PELP1, has the binding to RXRα binding was also by PELP1 which the of the binding was by the and The NR are that an by the coactivators to with the the in vitro binding studies that PELP1 utilize its NR to with the interaction of PELP1 with RXRα in the we by cellular the PELP1 well in we used which to the by antibody. and control cells were with 9-cis-RA or with the was the cell using an and proteins were by and with RXRα antibody. found that RXRα with and such interaction was by 9-cis-RA we the cell with and showed of PELP1 PELP1 was in the proteins were with control an of in we used and of PELP1, and RXRα was by of PELP1 and RXRα was by and The of PELP1 was in the with RXRα, and their was evident by to the of the the binding of PELP1 to RXRα homodimers to their consensus DNA was with nuclear pcDNA and PELP1 clones with 9-cis-RA using with with the nuclear in the of which the homodimer to the binding of RXRα to the was evident in both pcDNA and clones on 9-cis-RA and in comparison to and was a higher level of formation of in in comparison to pcDNA when with 9-cis-RA in comparison to The of RXRα in these clones were the same in a greater formation and stability of the DNA RXRα homodimers in the presence of studies have that of coactivators such as the stability of RXRα homodimers in response to 9-cis-RA A. S. Chambon P. B. PubMed Scopus Google Scholar). These that of PELP1 protein be to a of the formation and of RXRα homodimers on the which is a of the coactivator function of PELP1 in transcription. of the binding of PELP1 to the homodimers was by the supershift of the in the presence of PELP1 specific These on the that PELP1 and RXRα PELP1 of are antiproliferative and potential Cell. Sci. PubMed Scopus Google Scholar). 9-cis-RA, a specific of RXRα, is an important retinoid that has been for its M. Scholar). In the of that PELP1 was an interacting coactivator of RXRα, we PELP1 could the of WT, and were with 9-cis-RA or for and cell was showed that 9-cis-RA cell in the cell as by the in cell cells PELP1 exhibited significantly greater cell than or cells in response to 9-cis-RA This was evident by the of 9-cis-RA was in cell in PELP1 clones in comparison to in the of both pcDNA and clones higher of cell of the PELP1 clones in response to 9-cis-RA was evident in and the are an of the the extent of cell in these we also the cells in the in the and the cell by R. of of R. Scholar). that 9-cis-RA apoptosis in cells in comparison to the control of cells and showed a level of apoptosis in response to with 9-cis-RA a higher of cell in the cells also could be in the of the cells of 9-cis-RA the propensity of the cells with PELP1 expression to undergo we the of 9-cis-RA for on the of the cells using cell The is by cells which have DNA that These cells have DNA than the cells in or have DNA of the of are referred to as G. C. PubMed Scopus Google Scholar). cell studies showed significantly greater of the in both basal and cells than in or cells an was for apoptosis in these stable cell were with 9-cis-RA for and with a cells were identified by the to the binding of to which is to the of the in cells. In the of stable different were with both and and the of cells of cells was On 9-cis-RA the cells showed a higher of apoptosis of in comparison with pcDNA and cells of the same and of the cells is for comparison This confirmed that PELP1-overexpressing clones are to 9-cis-RA-induced apoptosis. these showed that the apoptosis by PELP1 was with the function of PELP1, as these effects were in pcDNA or clones. PELP1 Silencing of to 9-cis-RA-induced that expression of PELP1 9-cis-RA-induced we the of PELP1 expression using specific on the of 9-cis-RA to cell cells were with or control the cells were with 9-cis-RA for or with and cell were found a in the extent of cell in cells with PELP1 expression This reinforced the that PELP1 is an of 9-cis-RA-induced and of its expression compromised the susceptibility to effects of of the PELP1 expression in parental MCF-7 cells also in an of cells to undergo cell These that PELP1 is an of the 9-cis-RA-induced cell to coactivator function of PELP1 for the RXRα An of PELP1 expression in stable cell and in MCF-7 parental cell is evident by the for PELP1 in cell and PELP1 has the of the NR that with an increasing of other the of PELP1 to bind and function as a coactivator of RXRα, we the of PELP1 also transcription function of a RXRα of the that the heterodimer in of response and the resulting effects 2005; PubMed Scopus Google Scholar). The heterodimer to the and transcription in response to both and RXRα ligands. the of PELP1 on the found a of the in cells with expression of PELP1 in response to different and These the that PELP1 could function as a coactivator of the assay was in clones. found a of in cells as with the in or cells in response to with and was a of in cells with was a and of the and 9-cis-RA, of of were in the control pcDNA and cells the of PELP1 in the of activity. on the expression of which is a target was higher in cells in comparison to the in cells These that PELP1 could function as a coactivator of heterodimer in response to both and PPARγ-specific ligands. PELP1 and the to cell and cellular differentiation, and are as potential Scholar). the present study revealed a coactivator function of PELP1 for PPARγ, we to PELP1 could also the of and cells were with a of for and the cells were with to the extent of in cells. One of the effects of the differentiation in cells is to the of is a used to the extent of cellular differentiation a lipophilic is used to the showed that with in a of the in cells a of the was also in the cells. for the was in the cells either in the presence or of cells exhibited an higher in the presence of in response to the presence of in the the of that PELP1-overexpressing cells have a greater and of is known to a in cell and of D.J. A. PubMed Scopus Google Scholar), and a in the of is of the of cells. with we found that the level of protein in as well as in cells the extent of was in a higher propensity of PELP1-overexpressing cells to undergo differentiation in response to The binding of the hormone to the NR and the binding of the NR homodimer or heterodimer to specific DNA sequences the initial by which the NR the The of the signal is by the of the to coactivator which by their chromatin the chromatin to the transcription machinery, gene transcription. In it is that the level of and of the coactivator proteins the NR In addition to the mechanism of coactivator the of novel coactivators is also as the of the NR in the cell is the of several coactivators in cells. RXRα is a retinoid receptor that is by the specific 9-cis-RA and related functions as a homodimer as an heterodimeric partner of several other PPARγ, for RXRα is referred to as the which is by either PPARγ-specific C. D.J. R. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In the present we found that 9-cis-RA the expression of PELP1 gene and protein 1). This to be a of 9-cis-RA on PELP1 gene as transcription and the 9-cis-RA-induced PELP1 gene expression PELP1 was identified as a coactivator of (7Vadlamudi R.K. Wang R.-A. Mazumdar A. Kim Y. A. R. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and several recent revealed its function as an important transcriptional coregulatory protein S. R. R.K. 2000; Scopus Google Biol. Full Text Full Text PDF PubMed Scopus Google B. Wang R.-A. R. R.K. 2005; PubMed Scopus Google Scholar). the purpose of 9-cis-RA-induced PELP1 we found that PELP1 functions as a coactivator protein of RXRα, a receptor for 9-cis-RA in MCF-7 cells showed that PELP1 functioned as a coactivator of RXRα This was confirmed by the assay in PELP1-overexpressing higher of the in comparison to the pcDNA and clones was of expression of RXRα the clones showed that the was to PELP1 and to in the of RXRα in the cells higher expression of CRBP II, a RXRα target gene in in comparison to the cells on with 9-cis-RA reinforced One of the of a coactivator protein is that it with the This of the coactivator to NR and of target gene with was that PELP1 to RXRα its in and that 9-cis-RA of cells such interactions in the of PELP1 with RXRα and by the of these proteins in the nuclear reinforced PELP1 and RXRα as interacting in vivo. studies showed that PELP1 could with RXRα These the for PELP1 as a novel binding partner of RXRα, to coactivator function of are of cellular apoptosis and have been a of as and therapeutic M. M. 2001; PubMed Scopus Google Scholar). The function of PELP1 as a coactivator of RXRα to a potential for PELP1 in the effects of it was discovered that of PELP1 the susceptibility of cells to undergo apoptosis in response to 9-cis-RA PELP1 to 9-cis-RA-induced apoptosis that PELP1 be an important of the molecular machinery involved in of effects of RXRα, in addition to gene expression as a also functions as an heterodimer of several other is involved in the of and their ligands. The heterodimer of the most well NR in of the molecular and coactivator is also an important molecular target in as the have effects of their to cellular differentiation D.J. S. C. 1998; PubMed Scopus Google Scholar). RXRα and that be by specific to either of the In study also discovered that PELP1 also as a coactivator of the heterodimer in MCF-7 cells with of PELP1 showed that PELP1 the in response to and in stable cell exhibited greater of in clones in comparison to the pcDNA and the that PELP1 was a coactivator of heterodimer in clones in response to and 9-cis-RA, a and of was This was in comparison to a in response to the PPARγ-specific This be to the that the a is in response to 9-cis-RA and expression at consensus In addition to 9-cis-RA RXRα that are also of binding and transcription on Cell. Sci. PubMed Scopus Google Scholar). This be for the of in response to as a coactivator of PELP1 was also to the effects of as evident by the in the stable cell clones showed a of differentiation as evident by a of formation of in response to On the in study we have that PELP1 the effects of 9-cis-RA and PPARγ-specific by functioning as a coactivator of RXRα homodimers and 9-cis-RA also its effects by as a for which functions as a heterodimer with RXRα and to acid receptor response In addition to binding RXRα, it is that PELP1 also with and the effects of is also that PELP1 as coactivator of transcription at by binding to RXRα in the This a study and is in the present PELP1 was and identified as a coactivator of transcription (7Vadlamudi R.K. Wang R.-A. Mazumdar A. Kim Y. A. R. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). it was also found to function as a of receptor and transcription factors such as protein and complex response Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In the present we have the of PELP1 to bind to of the NR RXRα, and function as a transcriptional coactivator of RXRα homodimers and which are known to be involved in and In response to PELP1 is to to its in response to or PPARγ-specific ligand, PELP1 functions as a coactivator of RXRα homodimers and to their antiproliferative these the that cells utilize a of coactivators to facilitate signal to the of the a was identified and as a coactivator of P. R. M. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), it was found to function as a coactivator of transcriptional P. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The of transcriptional coregulatory proteins such as PELP1 to and the functions of several transcription factors the cell functions by coregulators the of coregulators for specific transcription we have revealed a novel facet of PELP1 function as a potentiator of antiproliferative effects of RXRα and PPARγ-specific it as a potential target for the This study has to a of by PELP1, to it as an important transcriptional coregulatory protein in the