Isolation and Characterization of Peroxisome Proliferator-activated Receptor (PPAR) Interacting Protein (PRIP) as a Coactivator for PPAR

Abstract

We previously isolated and identified steroid receptor coactivator-1 (SRC-1) and peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP/PPARBP) as coactivators for PPAR, using the ligand-binding domain of PPARγ as bait in a yeast two-hybrid screening. As part of our continuing effort to identify cofactors that influence the transcriptional activity of PPARs, we now report the isolation of a novel coactivator from mouse, designated PRIP (peroxisome proliferator-activated receptorinteracting protein), a nuclear protein with 2068 amino acids and encoded by 13 exons. Northern analysis showed that PRIP mRNA is ubiquitously expressed in many tissues of adult mice. PRIP contains two LXXLL signature motifs. The amino-terminal LXXLL motif (amino acid position 892 to 896) of PRIP was found to be necessary for nuclear receptor interaction, but the second LXXLL motif (amino acid position 1496 to 1500) appeared unable to bind PPARγ. Deletion of the last 12 amino acids from the carboxyl terminus of PPARγ resulted in the abolition of the interaction between PRIP and PPARγ. PRIP also binds to PPARα, RARα, RXRα, ER, and TRβ1, and this binding is increased in the presence of specific ligands. PRIP acts as a strong coactivator for PPARγ in the yeast and also potentiates the transcriptional activities of PPARγ and RXRα in mammalian cells. A truncated form of PRIP (amino acids 786–1132) acts as a dominant-negative repressor, suggesting that PRIP is a genuine coactivator. We previously isolated and identified steroid receptor coactivator-1 (SRC-1) and peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP/PPARBP) as coactivators for PPAR, using the ligand-binding domain of PPARγ as bait in a yeast two-hybrid screening. As part of our continuing effort to identify cofactors that influence the transcriptional activity of PPARs, we now report the isolation of a novel coactivator from mouse, designated PRIP (peroxisome proliferator-activated receptorinteracting protein), a nuclear protein with 2068 amino acids and encoded by 13 exons. Northern analysis showed that PRIP mRNA is ubiquitously expressed in many tissues of adult mice. PRIP contains two LXXLL signature motifs. The amino-terminal LXXLL motif (amino acid position 892 to 896) of PRIP was found to be necessary for nuclear receptor interaction, but the second LXXLL motif (amino acid position 1496 to 1500) appeared unable to bind PPARγ. Deletion of the last 12 amino acids from the carboxyl terminus of PPARγ resulted in the abolition of the interaction between PRIP and PPARγ. PRIP also binds to PPARα, RARα, RXRα, ER, and TRβ1, and this binding is increased in the presence of specific ligands. PRIP acts as a strong coactivator for PPARγ in the yeast and also potentiates the transcriptional activities of PPARγ and RXRα in mammalian cells. A truncated form of PRIP (amino acids 786–1132) acts as a dominant-negative repressor, suggesting that PRIP is a genuine coactivator. peroxisome proliferator-activated receptor steroid receptor coactivator-1 PPAR-interacting protein truncated PRIP glutathione S-transferase retinoid-X receptor for 9-cis-retinoic acid estrogen receptor thyroid hormone (T3) receptor polymerase chain reaction rapid amplification of cDNA ends kilobase(s) mouse CREB-binding protein PPAR-binding protein bacterial artificial chromosome Peroxisome proliferator-activated receptors (PPARs)1 are members of the nuclear receptor superfamily that regulates the expression of target genes, in particular those associated with lipid metabolism (1.Issemann J. Green S. Nature. 1990; 347: 645-650Crossref PubMed Scopus (3046) Google Scholar, 2.Chu R. Reddy J.K. Ann. N. Y. Acad. Sci. 1996; 804: 176-201Crossref PubMed Scopus (100) Google Scholar, 3.Mangelsdorf 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 (6085) Google Scholar). PPARs, which derive the designation by virtue of their ability to mediate predictable pleiotropic effects in response to peroxisome proliferators (2.Chu R. Reddy J.K. Ann. N. Y. Acad. Sci. 1996; 804: 176-201Crossref PubMed Scopus (100) Google Scholar, 4.Reddy J.K. Lalwani N.D. CRC Crit. Rev. Toxicol. 1983; 12: 1-58Crossref Scopus (869) Google Scholar), consist of three isotypes, namely PPARα, PPARδ (also called PPARβ), and PPARγ, which are products of separate genes (1.Issemann J. Green S. Nature. 1990; 347: 645-650Crossref PubMed Scopus (3046) Google Scholar, 5.Dreyer C. Krey G. Keller H. Givel F. Helftenbein G. Wahli W. Cell. 1992; 68: 879-887Abstract Full Text PDF PubMed Scopus (1206) Google Scholar, 6.Zhu Y. Qi C. Korenberg J.R. Chen X-N. Noya D. Rao M.S. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7921-7925Crossref PubMed Scopus (604) Google Scholar, 7.Kliewer S.A. Forman B.M. Blumberg B. Ong E.S. Borgmeyer U. Mangelsdorf D.J. Umesono K. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7355-7359Crossref PubMed Scopus (1280) Google Scholar). These PPAR isotypes appear to exhibit distinct patterns of tissue distribution and differ considerably in their ligand-binding domains, implying that they possibly perform different functions in different cell types (5.Dreyer C. Krey G. Keller H. Givel F. Helftenbein G. Wahli W. Cell. 1992; 68: 879-887Abstract Full Text PDF PubMed Scopus (1206) Google Scholar, 6.Zhu Y. Qi C. Korenberg J.R. Chen X-N. Noya D. Rao M.S. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7921-7925Crossref PubMed Scopus (604) Google Scholar, 7.Kliewer S.A. Forman B.M. Blumberg B. Ong E.S. Borgmeyer U. Mangelsdorf D.J. Umesono K. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7355-7359Crossref PubMed Scopus (1280) Google Scholar, 8.Braissant O. Foufelle F. Scotto C. Dauca M. Wahli W. Endocrinology. 1996; 137: 354-366Crossref PubMed Scopus (1737) Google Scholar, 9.Jain S. Pulikuri S. Zhu Y. Qi C. Kanwar Y.S. Yeldandi A.V. Rao M.S. Reddy J.K. Am. J. Pathol. 1998; 153: 349-354Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Of the three isotypes, PPARα expression is relatively high in hepatocytes, enterocytes, and the proximal tubular epithelium of kidney when compared with other cell types (8.Braissant O. Foufelle F. Scotto C. Dauca M. Wahli W. Endocrinology. 1996; 137: 354-366Crossref PubMed Scopus (1737) Google Scholar), and evidence derived from mice with PPARα gene disruption indicates that this receptor is essential for the pleiotropic responses induced by peroxisome proliferators (10.Lee S.S.-T. Pineau T. Drago J. Lee E. Owens J.W. Kroetz D.L. Fernandez-Salguero P.M. Westphal H. Gonzalez F. Mol. Cell. Biol. 1995; 15: 3012-3022Crossref PubMed Scopus (1500) Google Scholar). Also worth noting is that the fatty acyl-CoA oxidase, the first and the rate-limiting enzyme of the peroxisomal fatty acid β-oxidation system, plays a critical role in the metabolism of biological/natural ligands of PPARα in that mice with fatty acyl-CoA oxidase gene disruption exhibit sustained spontaneous up-regulation of PPARα-responsive genes (11.Fan C-Y. Pan J. Usuda N. Yeldandi A.V. Rao M.S. Reddy J.K. J. Biol. Chem. 1998; 273: 15639-15645Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar). PPARδ isotype is ubiquitously expressed in the adult tissues and binds the same ligands as other PPARs (7.Kliewer S.A. Forman B.M. Blumberg B. Ong E.S. Borgmeyer U. Mangelsdorf D.J. Umesono K. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7355-7359Crossref PubMed Scopus (1280) Google Scholar, 12.Forman B.M. Chen J. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4313-4317Google Scholar, 13.Kliewer S.A. Sundseth S.S. Jones S.A. Brown P.J. Wisely G.B. Koble C.S. Devchand P. Wahli W. Willson T.M. Lenhard J.M. Lehman J.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4318-4323Crossref PubMed Scopus (1893) Google Scholar). Recent evidence suggests that nonsteroidal anti-inflammatory drugs inhibit colon carcinogenesis through inhibition of PPARδ and that PPARδ functions as a target for adenomatous polyposis coli (14.He T-C. Chan T.A. Vogelstein B. Kinzler K.W. Cell. 1999; 99: 335-345Abstract Full Text Full Text PDF PubMed Scopus (1034) Google Scholar). PPARγ, which is expressed predominantly in adipose tissue, as well as in certain epithelial cells such as those of the colonic mucosa, mammary epithelium, and urinary bladder (8.Braissant O. Foufelle F. Scotto C. Dauca M. Wahli W. Endocrinology. 1996; 137: 354-366Crossref PubMed Scopus (1737) Google Scholar, 9.Jain S. Pulikuri S. Zhu Y. Qi C. Kanwar Y.S. Yeldandi A.V. Rao M.S. Reddy J.K. Am. J. Pathol. 1998; 153: 349-354Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), plays a pivotal role in adipocyte development and lipid homeostasis (15.Tontonoz P. Hu E. Spiegelman B.M. Cell. 1994; 79: 1147-1156Abstract Full Text PDF PubMed Scopus (3122) Google Scholar, 16.Barak Y. Nelson M.C. Ong E.S. Jones Y.Z. Ruiz-lozano P. Chien K.R. Koder A. Evans R.M. Mol. Cell. 1999; 4: 589-595Abstract Full Text Full Text PDF Scopus (1651) Google Scholar, 17.Kubota N. Terauchi Y. Miki H. Tamemoto H. Yamauchi T. Komeda K. Saton S. Nakano R. Ishii C. Sugiyama T. Eto K. Tsubamoto Y. Okuno A. Murakami K. Sekihara H. Hasegawa G. Naito M. et al.Mol. Cell. 1999; 4: 597-609Abstract Full Text Full Text PDF PubMed Scopus (1220) Google Scholar). Although a great deal is known about genes regulated by PPARα, especially in conjunction with peroxisome proliferator-induced pleiotropic responses (2.Chu R. Reddy J.K. Ann. N. Y. Acad. Sci. 1996; 804: 176-201Crossref PubMed Scopus (100) Google Scholar), there is very little information on PPARγ- and PPARδ-regulated genes in specific cell types, despite the fact that many of the ligands identified to date interact with one or more PPAR isotypes (12.Forman B.M. Chen J. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4313-4317Google Scholar, 13.Kliewer S.A. Sundseth S.S. Jones S.A. Brown P.J. Wisely G.B. Koble C.S. Devchand P. Wahli W. Willson T.M. Lenhard J.M. Lehman J.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4318-4323Crossref PubMed Scopus (1893) Google Scholar). Evidence accumulated so far indicates that the transcriptional activation of nuclear receptors after ligand binding involves the participation of cofactors termed nuclear receptor and coactivators 1999; PubMed Scopus Google Scholar, C. Zhu Y. Reddy J.K. PubMed Scopus Google Scholar). The suggests that receptors are in a by nuclear receptor such as T. J. B. R. A. Y. M. Nature. 1995; PubMed Scopus Google and Evans R.M. Nature. 1995; PubMed Scopus Google Scholar). ligand the from the nuclear the nuclear receptor to a of called nuclear receptor that the nuclear receptors with 1999; PubMed Scopus Google Scholar). The coactivators identified in the which three S.A. 1995; PubMed Scopus Google Scholar, Y. T. J. R. B. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Qi C. C. Rao M.S. Reddy J.K. 1996; Google Scholar), C. Chambon P. H. J. 1996; 15: PubMed Scopus Google Scholar, J. J. Y. S. Nature. 1997; PubMed Scopus Google and J. J. Y. S. Nature. 1997; PubMed Scopus Google Scholar, H. D. A. Y. Evans R.M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. G. J.M. 1997; PubMed Scopus Google Scholar, H. P.J. Chen Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google D. Nelson M.C. T. H. M. Evans R.M. Nature. 1996; PubMed Scopus Google Scholar, G. N. R. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google S. F. G. S. P.J. J. 1995; PubMed Scopus Google Y. Qi C. S. Rao M.S. Reddy J.K. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google and P. R. M. Spiegelman B.M. Cell. 1998; 92: Full Text Full Text PDF PubMed Scopus Google 1999; PubMed Scopus Google Scholar). of nuclear receptor coactivators the LXXLL amino motif that of nuclear receptor J. J. Y. S. Nature. 1997; PubMed Scopus Google Scholar, E. S. Nature. 1997; PubMed Scopus Google Scholar). of the and activities that the G. S.A. Nature. 1997; PubMed Scopus Google Scholar, Y. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. R. M. T.M. 1998; PubMed Scopus Google Scholar, T. Nature. 1996; PubMed Scopus Google Scholar). The and analysis of many of the known nuclear receptor coactivators resulted from the yeast two-hybrid S.A. 1995; PubMed Scopus Google Scholar, Y. Qi C. C. Rao M.S. Reddy J.K. 1996; Google Scholar, Y. Qi C. S. Rao M.S. Reddy J.K. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, P. R. M. Spiegelman B.M. Cell. 1998; 92: Full Text Full Text PDF PubMed Scopus Google Scholar). that on the and of the transcriptional information the transcriptional activation of thyroid hormone receptor and other transcriptional M. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, M. S. W. S. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. H. P. Nature. 1999; PubMed Scopus Google Scholar, S. S. W. R. Nature. 1999; PubMed Scopus Google Scholar). The thyroid hormone the activity of the M. S. W. S. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). protein such as receptor and are identified and found to be for the transcriptional activation of and nuclear receptors C. M. H. P. Nature. 1999; PubMed Scopus Google Scholar, S. S. W. R. Nature. 1999; PubMed Scopus Google Scholar). is of that this acts on the nuclear receptors by binding to a nuclear receptor coactivator we identified as a coactivator for PPAR Y. Qi C. S. Rao M.S. Reddy J.K. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). we that the gene is in about of and the gene amplification was in about of Y. Qi C. S. R. G.B. Yeldandi A.V. Rao M.S. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). These the of nuclear receptor coactivators in transcriptional activation and also to their role in we report the of a nuclear receptor designated PRIP identified yeast two-hybrid screening. PRIP contains two LXXLL signature amino acid and but the motif appear necessary for binding to PPARγ. PRIP acts as a strong coactivator for PPARγ in yeast and also potentiates transcriptional activities of PPARγ and RXRα in mammalian cells. We that a truncated form of PRIP (amino acids 786–1132) functions as a dominant-negative repressor, suggesting that PRIP is a genuine coactivator. and as well as the for in of RARα, TRβ1, and ER, Y. Qi C. S. Rao M.S. Reddy J.K. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). and by R. Evans was by the of PRIP cDNA the of was by PRIP cDNA with two the carboxyl terminus of was by the PRIP cDNA the of The and by the from isolated by the yeast two-hybrid the of a a nuclear and A cDNA a that with PPARγ was isolated by yeast two-hybrid of a mouse cDNA as previously Y. Qi C. C. Rao M.S. Reddy J.K. 1996; Google Scholar, Y. Qi C. S. Rao M.S. Reddy J.K. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). We the cDNA from a mouse kidney cDNA with using a from to the The products and three The cDNA that we designated or peroxisome receptor to ability to bind PPARs and to from which we Y. Qi C. S. Rao M.S. Reddy J.K. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). tissue Northern of in was with PRIP cDNA to the by the a mouse with and one the PRIP gene was The was with the and as The and by enzyme and a of between the cDNA and yeast on in the presence or of a PPARγ and for in of of cells in was by and activity was by a The and and coli and to to the was using and a a of protein on was with of in for in of The binding was in the presence or specific for PPARγ, 9-cis-retinoic acid for RXRα and RARα, for PPARα, for TRβ1, and for ER, three with binding by for in of by and cells with or with by the after the cell was The was with or The on and to cells in and in for for with of of the expression and of expression using after and for and cells in for and with with for cells three with and with a the PPARγ ligand-binding domain as a bait in the yeast two-hybrid system, we isolated from a mouse cDNA a cDNA a PPAR-interacting designated The PRIP cDNA was through of that a protein of 2068 amino acids with of contains two LXXLL that to be essential for transcriptional coactivators to interact with nuclear receptors J. J. Y. S. Nature. 1997; PubMed Scopus Google Scholar, E. S. Nature. 1997; PubMed Scopus Google Scholar). motif is amino acid and the second is amino acid The PRIP cDNA by yeast two-hybrid amino acids and contains the first LXXLL the amino acid of PRIP was compared with known in showed to that the first amino acids in the The cDNA was isolated from cells T. N. K. A. N. 1996; PubMed Scopus Google Scholar). The of this protein PRIP contains a of from amino acids The PRIP was expressed as in tissues and A high of expression of PRIP mRNA in the A second is in the which for of a two to the of PRIP protein cells the nuclear of the expressed PRIP protein analysis of PRIP mouse tissue Northern of for tissue was PRIP cDNA and to with for The of PRIP is in tissues is in the of expressed PRIP in cells. to the carboxyl terminus of the PRIP and expressed in cells. The was using the nuclear of PRIP the PRIP a mouse was first by using a of the PRIP The of the and the by and by The PRIP gene of 13 and about to the gene of and about of the PRIP cDNA is encoded by a The of of the and to the for R. C. K. F. Chambon P. Proc. Natl. Acad. Sci. U. S. A. of mouse PRIP in a We the influence of PPARγ ligand on the binding of PRIP to PPARγ in (amino acids which was isolated by yeast two-hybrid and expressed as the protein with the activation was with yeast and the activity as of the of interaction in the presence or of the of we interaction between PRIP and PPARγ, which resulted in in the activity The presence of the ligand this interaction between PRIP and PPARγ, to in the activity The of the ligand-binding domain the nuclear receptors to be essential for the transcriptional activation D.J. Evans R.M. Cell. 1995; 83: Full Text PDF PubMed Scopus Google Scholar). this is for the binding of PPARγ to which the last 12 amino acids from the carboxyl terminus of PPARγ, was with The presence of PRIP to in activity in the presence or of the that the the ability of PPARγ to bind PRIP As LXXLL is the signature motif for the binding of to nuclear we the second LXXLL in the PRIP bind to PPARγ. a protein between activation domain and the PRIP cDNA (amino acids the second was with The presence of the second LXXLL motif the activity of we that the second LXXLL motif is necessary for the interaction between PRIP and PPARγ, but the first LXXLL motif necessary and The interaction between PRIP and PPARγ was by in binding with protein and in Although the but the PRIP in the presence and of PPARγ ligand the of the ligand this interaction PRIP also showed the interaction with RXRα, RARα, ER, and TRβ1, as well as PPARα PPARγ and PRIP form a in the of a PRIP with a was and expressed in cell derived from kidney The was with and by using the interaction between PPARγ and PRIP in A that (amino acids 786–1132) the first LXXLL but (amino acids which contains the second LXXLL with PPARγ in PRIP acts as a coactivator in the the was with PRIP in yeast PRIP the transcriptional activity of PPARγ in the of ligand the is in the presence of ligand PRIP as a coactivator for PPARγ in mammalian we PRIP in cells with PPARγ and the transcriptional activity of PPARγ with expression of the peroxisome response PRIP increased the of the gene by about in the presence of PRIP was with RXRα, increased the of RXRα by PRIP as a coactivator for PPARγ, we in a truncated form of PRIP amino acids which contains the first LXXLL and to interact with PPARγ. of resulted in a in a of in the presence of was in the of the ligand (amino which contains the second LXXLL motif that bind PPARγ, inhibit the transcriptional activity of PPARγ. the of be by with with RXRα, the of truncated PRIP on the transcriptional activity was in with PPARγ a yeast two-hybrid with as bait to a mouse cDNA we isolated a cDNA designated as which is a nuclear protein with 2068 amino this we on the of this coactivator which a strong ligand and interaction with PPARγ and other nuclear receptors The PRIP gene of 13 and Northern analysis showed that PRIP mRNA is ubiquitously expressed in adult mouse PRIP to interact with PPARγ, which the last 12 amino acids the carboxyl terminus of the ligand-binding is for the transcriptional activation of the nuclear receptors but for the hormone binding and D.J. Evans R.M. Cell. 1995; 83: Full Text PDF PubMed Scopus Google Scholar). the role for PRIP as a coactivator for PPARγ, many coactivators interact with the domain of nuclear PRIP contains two LXXLL that to be necessary and for the binding of cofactors to nuclear receptors J. J. Y. S. Nature. 1997; PubMed Scopus Google Scholar, E. S. Nature. 1997; PubMed Scopus Google Scholar). we found that one of LXXLL is necessary for the interaction of PRIP with the nuclear We found that the second LXXLL motif is unable to bind to Although truncated which contains the first LXXLL binds to PPARγ, on of the binding and the analysis of this motif are to the in PRIP protein that a role in we found a of in a of are critical to such as M. E. N. 1997; PubMed Scopus Google Scholar). the of is more and the as Also of is the fact that a of in nuclear receptor coactivator H. D. A. Y. Evans R.M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. G. J.M. 1997; PubMed Scopus Google Scholar). protein and receptor of and C.S. J. PubMed Scopus Google Scholar, G. Y. J. 1994; PubMed Scopus Google Scholar). is that the LXXLL interaction between coactivators and nuclear the high between especially with protein C.S. J. PubMed Scopus Google Scholar). We found that PRIP functions as a coactivator in the yeast when compared with coactivator activity in the mammalian cells in this be in part by the of the coactivator by other in mammalian cell and the of of in also be to the fact that mammalian cells contains to a PRIP protein in We also found PRIP in the this contains many different nuclear implying that PRIP possibly the as a of a more transcriptional in PRIP was to the transcriptional activity of RXRα to a that of PPARγ. with this is the that the truncated form of PRIP a on the transcriptional activation of RXRα as compared with PPARγ. is that PRIP more to the transcriptional activation to PPARγ certain As PRIP also binds to PPARα, RARα, RXRα, ER, and TRβ1, and as this binding is increased in the presence of specific we PRIP to as a coactivator for a of nuclear The of the coactivator to on the of a nuclear receptor and the cell is now evidence to the that the transcriptional activation of nuclear receptors involves two of nuclear receptor termed and coactivators (1.Issemann J. Green S. Nature. 1990; 347: 645-650Crossref PubMed Scopus (3046) Google Scholar). are associated with receptors to mediate the ligand binding the of from the nuclear the nuclear receptors coactivators to The coactivators identified so far be two The first of such as those to the and activities and as a are in the of G. S.A. Nature. 1997; PubMed Scopus Google Scholar, Y. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. R. M. T.M. 1998; PubMed Scopus Google Scholar, T. Nature. 1996; PubMed Scopus Google Scholar). The second of which are of appear to as the the receptor to the (1.Issemann J. Green S. Nature. 1990; 347: 645-650Crossref PubMed Scopus (3046) Google Scholar). this which we and as a nuclear receptor coactivator Y. Qi C. S. Rao M.S. Reddy J.K. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), found to be a critical of the M. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, M. S. W. S. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. H. P. Nature. 1999; PubMed Scopus Google Scholar, S. S. W. R. Nature. 1999; PubMed Scopus Google and more to be in the second of the receptors with the which we now is part of or transcriptional to be The for the of a of coactivators is that different coactivators in the of specific target genes, as by the that and to exhibit target gene H. R. K. R. Nature. 1998; PubMed Scopus Google Scholar). is also that specific nuclear receptors a distinct of coactivators for transcriptional activity and that such a of coactivators for other members of the nuclear receptor superfamily of novel in peroxisome J.K. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google and other that D.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). mice are and and exhibit a or when for certain nuclear receptor functions C. Zhu Y. Pan J. Yeldandi A.V. Rao M.S. N. Pulikuri S. T. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google J. Y. 1998; PubMed Scopus Google Scholar), suggesting the other mice with gene Y. Qi C. Y. Rao M.S. Reddy J.K. J. Biol. Chem. Scholar). we also found and amplification of the gene in Y. Qi C. S. R. G.B. Yeldandi A.V. Rao M.S. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). nuclear receptor H. D. A. Y. Evans R.M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. G. J.M. 1997; PubMed Scopus Google Scholar), was also found and in J. G. J.M. 1997; PubMed Scopus Google Scholar). These the role of coactivators in cell and are to the role of PRIP in development and this gene is also and in certain of our we found that PRIP is to nuclear receptor coactivator and J. Biol. Chem. and S. O. J. J. Y. P. and J. W. J. Biol. Chem. We M. Evans for We also the of W. and the of