FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2023697788> ?p ?o ?g. }

• W2023697788 endingPage "3840" @default.
• W2023697788 startingPage "3836" @default.
• W2023697788 abstract "We have cloned two human peroxisome proliferator- activated receptor (PPAR) subtypes, hPPARα and hNUC1. hPPARα is activated by clofibric acid and other PPAR activators. hNUC1 is not activated by these compounds acting instead as a repressor of hPPARα and human thyroid hormone receptor transcriptional activation. Repression is specific since hNUC1 does not significantly repress activation by the progesterone or retinoic acid receptors. We demonstrate co-operative binding of hNUC1 and hRXRα to a PPAR-responsive element and show that in the presence of hRXRα, the affinity of hNUC1 for the peroxisome proliferator is comparable to that of hPPARα. Furthermore, repression of hPPARα can be overcome by transfecting excess hPPARα. We propose that hNUC1 represses the activity of hPPARα by titrating out a factor required for activation. Our data further suggests convergence of thyroid hormone- and peroxisome-mediated fatty acid metabolism pathways. Overcoming hNUC1 repression could be a means of increasing the activity of these receptors. We have cloned two human peroxisome proliferator- activated receptor (PPAR) subtypes, hPPARα and hNUC1. hPPARα is activated by clofibric acid and other PPAR activators. hNUC1 is not activated by these compounds acting instead as a repressor of hPPARα and human thyroid hormone receptor transcriptional activation. Repression is specific since hNUC1 does not significantly repress activation by the progesterone or retinoic acid receptors. We demonstrate co-operative binding of hNUC1 and hRXRα to a PPAR-responsive element and show that in the presence of hRXRα, the affinity of hNUC1 for the peroxisome proliferator is comparable to that of hPPARα. Furthermore, repression of hPPARα can be overcome by transfecting excess hPPARα. We propose that hNUC1 represses the activity of hPPARα by titrating out a factor required for activation. Our data further suggests convergence of thyroid hormone- and peroxisome-mediated fatty acid metabolism pathways. Overcoming hNUC1 repression could be a means of increasing the activity of these receptors. Peroxisomes are subcellular organelles found in animals and plants, and they contain enzymes for respiration, cholesterol, and lipid metabolism. A variety of chemical agents including hypolipidemic drugs such as clofibrates cause proliferation of peroxisomes in rodents (1Reddy J.K. Azarnoff D.L. Nature. 1980; 283: 397-398Crossref PubMed Scopus (780) Google Scholar). Two hypotheses have been put forward to explain the mechanism of peroxisome proliferation. The first is the “lipid overload hypothesis” whereby an increase in the intracellular concentration of fatty acids is the main stimulus for peroxisome proliferation(2Nestel P.J. Ann. Rev. Nutr. 1990; 10: 149-167Crossref PubMed Scopus (197) Google Scholar, 3Phillipson B.E. Rothrock D.W. Connor W.E. Harris W.S. Illingworth D.R. N. Engl. J. Med. 1985; 312: 1210-1216Crossref PubMed Scopus (648) Google Scholar). The second hypothesis postulates a receptor-mediated mechanism and an as yet unidentified ligand. In supporting the second postulate, peroxisome proliferator-activated receptors (PPARs) 1The abbreviations used are: PPARperoxisome proliferator-activated receptorPRprogesterone receptorRARretinoid acid receptorRXRretinoid X receptorTRthyroid hormone receptorPPREperoxisome proliferator-responsive elementTREpthyroid hormone-responsive element (palindromic)ETYA5,8,11,14-eicosatetraynoic acidATRAall-trans-retinoic acidCFAclofibric acidGRglucocorticoid receptor. have been cloned from various species(4Isseman I. Green S. Nature. 1990; 347: 645-650Crossref PubMed Scopus (3059) Google Scholar, 5Dreyer C. Krey G. Hansjorg K. Givel F. Helftenbein G. Wahli W. Cell. 1992; 68: 879-887Abstract Full Text PDF PubMed Scopus (1214) Google Scholar, 6Gottlicher M. Widmar E. Li Q. Gustafsson J.A. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4653-4657Crossref PubMed Scopus (800) Google Scholar, 7Sher T. Yi H.F. McBride W.O. Gonzales F.J. Biochemistry. 1993; 32: 5598-5604Crossref PubMed Scopus (452) Google Scholar, 8Schmidt A. Endo N. Rutledge S.J. Vogel R. Shinar D. Rodan G.A. Mol. Endocrinol. 1992; 6: 1634-1641Crossref PubMed Scopus (366) Google Scholar). peroxisome proliferator-activated receptor progesterone receptor retinoid acid receptor retinoid X receptor thyroid hormone receptor peroxisome proliferator-responsive element thyroid hormone-responsive element (palindromic) 5,8,11,14-eicosatetraynoic acid all-trans-retinoic acid clofibric acid glucocorticoid receptor. We are interested in the effect of various fibrates on human PPAR subtypes. We have isolated two human PPAR subtypes hPPARα and hNUC1. While hPPARα is a transcriptional activator in the presence of fibrates and ETYA, hNUC1 is not. However, transfected hNUC1 decreased the response from endogenous PPARs. We therefore reasoned that one function of hNUC1 could be to repress the activity of hPPARα. Accordingly, experiments were performed to determine whether hNUC1 represses hPPARα and other members of the nuclear receptor family. We demonstrate that hNUC1 acts as a repressor of hPPARα and human thyroid hormone receptor activity. ETYA, ATRA, LT3, and CFA were purchased from Sigma, and WY-14,643 from Chemsyn Science Laboratories, Lenexa, KS. Stock solutions of these compounds were made in ethanol or methanol. A human homolog of rat PPARα was isolated from a human liver 5′-stretch λgt10 cDNA library (Clontech). The library was screened at medium stringency (40% formamide, 5 × SSC at 37°C), with a rPPAR nick-translated DNA fragment specific to the A/B and DNA binding domain (from the EcoRI to the BglII site, nucleotides 450-909) (6Gottlicher M. Widmar E. Li Q. Gustafsson J.A. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4653-4657Crossref PubMed Scopus (800) Google Scholar). Positive clones were isolated and subcloned into the Bluescript KS vector (Stratagene) for sequencing. The sequence is identical to that published by Sher et al.(7Sher T. Yi H.F. McBride W.O. Gonzales F.J. Biochemistry. 1993; 32: 5598-5604Crossref PubMed Scopus (452) Google Scholar) except for two amino acid differences, alanine at position 268 and glycine at position 296(28Mukherjee R. Jow L. Noonan D. McDonnell D.P. J. Steroid Biochem. Mol. Biol. 1994; 51: 157-166Crossref PubMed Scopus (263) Google Scholar). A second human PPAR subtype hNUC1 was isolated from a human kidney cDNA library by similarly screening with a probe specific to the rat PPAR DNA binding domain (from the PvuII to the BglII site, nucleotides 618-909) (6Gottlicher M. Widmar E. Li Q. Gustafsson J.A. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4653-4657Crossref PubMed Scopus (800) Google Scholar) as described above. A recombinant clone was isolated, subcloned into pGEM-5Zf (Promega), and sequenced. The sequence of this receptor is identical to that of the hNUC1 sequence (8Schmidt A. Endo N. Rutledge S.J. Vogel R. Shinar D. Rodan G.A. Mol. Endocrinol. 1992; 6: 1634-1641Crossref PubMed Scopus (366) Google Scholar) except for alanine at position 292. For expression in mammalian cells, the hPPARα cDNA was cloned into the NotI site of pBKCMV (Stratagene) to give pCMVhPPARα. The hNUC1 cDNA was directionally cloned into the SalI-SacII site of pBKCMV to give pCMVhNUC1. The reporter plasmid pPPREA3-tk-LUC containing three copies of the “A” site identified in the acyl-CoA oxidase gene regulatory sequence (9Osumi T. Wen J. Hashimoto T. Biochem. Biophys. Res. Commun. 1991; 175: 866-871Crossref PubMed Scopus (184) Google Scholar) has been described(10Kliewer S.A. Umesono K. Noonan D.J. Heyman R.A. Evans R.M. Nature. 1992; 358: 771-774Crossref PubMed Scopus (1525) Google Scholar). This PPRE conforms to the DR1 configuration(26Umsono K. Murakami K.K. Thompson C.C. Evans R.M. Cell. 1991; 65: 1255-1266Abstract Full Text PDF PubMed Scopus (1497) Google Scholar). The reporter plasmid AOX-LUC (10Kliewer S.A. Umesono K. Noonan D.J. Heyman R.A. Evans R.M. Nature. 1992; 358: 771-774Crossref PubMed Scopus (1525) Google Scholar) contains nucleotides −602 to +20 of the rat AOX promoter. The plasmids pRShRARα, pSVhPRB, and pRShTRβ and the reporters MTV-TREp2 and PRE2-tk-LUC have been described(11Giguere V. Ong E.S. Segui P. Evans R.M. Nature. 1987; 330: 624-629Crossref PubMed Scopus (1538) Google Scholar, 12Vegeto E. Shahbaz M.M. Wen D.X. Goldman M.E. O'Malley B.W. McDonnell D.P. Mol. Endocrinol. 1993; 7: 1244-1255Crossref PubMed Scopus (556) Google Scholar, 13Thomson C.C. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3494-3498Crossref PubMed Scopus (127) Google Scholar, 14Umesono K. Giguere V. Glass C.K. Rosenfeld M.G. Nature. 1988; 336: 262-265Crossref PubMed Scopus (428) Google Scholar). The human TRα1 cDNA (15Nakai A. Sakurai A. Bell G.I. DeGroot L.J. Mol. Endocrinol. 1988; 2: 1087-1092Crossref PubMed Scopus (92) Google Scholar) was liberated from pME21 by digestion with EcoRI and blunt-ended by digestion with mung bean nuclease. pRS plasmid (16Giguere V. Hollenberg S.M. Rosenfeld M.G. Evans R.M. Cell. 1986; 46: 645-652Abstract Full Text PDF PubMed Scopus (678) Google Scholar) was digested with BamHI, dephosphorylated, and repaired with Klenow enzyme. The TRα1 cDNA was was then joined to the vector by blunt end ligation. The reporter TRE(DR4)2-tk-LUC was made by inserting two copies of an oligonucleotide containing the TRE (DR4) sequence into the pBL-tk-LUC reporter(27Dana S.L. Hoener P.A. Wheeler D.A. Lawrence C.B. McDonnell D.P. Mol. Endocrinol. 1994; 8: 1193-1207Crossref PubMed Scopus (76) Google Scholar). The sequence of the DR4 oligonucleotide is 5′-GATCTAGGTCACAGGAGGTCACG-3′. HepG2 cells were grown in Dulbecco's modified Eagle's medium supplemented with 10% (v/v) fetal bovine serum (HyClone), 2 mML-glutamine, and 55 μg/ml gentamicin (BioWhittaker). Cells were plated at 1.7 × 105 cells/well for HepG2 in 12-well cell culture dishes (Costar). The medium was replaced with fresh medium 20 h later. After 4 h, DNA was added by the calcium phosphate coprecipitation technique (17Berger T.S. Parandosh Z. Perry B. Stein R.B. J. Steroid Biochem. Mol. Biol. 1992; 41: 733-738Crossref PubMed Scopus (80) Google Scholar). Typically, 0.1 μg of expression plasmid, 0.5 μg of the β-galactosidase expression plasmid pCH110 (internal control), and 0.5 μg of reporter plasmid were added to each well. Where indicated, 0-0.5 μg of hNUC1 plasmid (repressor) was added. Repressor plasmid dosage was kept constant by the addition of appropriate amounts of the empty expression vector pBKCMV. The total amount of DNA was kept at 2 μg by the addition of pGEM DNA. After 14 h the cells were washed with 1 × phosphate-buffered saline and fresh medium added (Dulbecco's modified Eagle's medium with 10% charcoal-stripped fetal bovine serum (HyClone) plus the above supplements). Ligands or PPAR activators were added to the final concentrations indicated. Control cells were treated with vehicle. After another 24 h the cells were harvested, and the luciferase and β-galactosidase activities were quantified on a Dynatech ML 1000 luminometer and a Beckman Biomek 1000 workstation, respectively. The normalized response is the luciferase activity of the extract divided by the β-galactosidase activity of the same. Each data point is the mean of triplicate transfections, and the error bars represent the standard deviation from the mean. Each experiment has been repeated at least three times and a representative experiment is shown in each case. hPPARα and hNUC1 were made by coupled in vitro transcription/translation using 1 μg of pCMVhPPARα or pCMVhNUC1 plasmid DNA and the T3-coupled reticulocyte lysate system (Promega). The baculovirus/Sf21 cell system was used to express hRXRα(18Allegretto E.A. McClurg M.R. Lazarchik S.B. Clemm D.L. Kerner S.A. Elgort M.G. Boehm M.F. White S. Pike J.W. Heyman R.A. J. Biol. Chem. 1993; 268: 1-9PubMed Google Scholar). Gel retardation assays were performed by incubating 1 μl of in vitro translated hPPARα or hNUC1 and 2 μg of hRXRα in buffer containing 10 mM Hepes (pH 7.8), 50 mM KCl, 1 mM dithiothreitol, 2.5 mM MgCl2, 0.4 mg/ml poly(dI-dC), and 20% glycerol at 4°C for 5 min. About 12 fmol of 32P-end-labeled probe (approximately 100,000 cpm) were then added and incubated at 25°C for another 5 min. Protein-DNA complexes were resolved by electrophoresis on 5% polyacrylamide gels in 0.5 × TBE. For the competition assays, annealed, unlabeled oligonucleotides were mixed with the labeled probe just before adding to the binding reactions. Oligonucleotides containing the PPRE sequence from the acyl-CoA oxidase (AOX) gene used as probe have the sequence 5′-CTAGCGATATCATGACCTTTGTCCTAGGCCTC-3′ (upper strand) and 5′-CTAGGAGGCCTAGGACAAAGGTCATGATATCG-3′ (lower strand). Oligonucleotides with sequences unrelated to the PPRE were used to determine specificity of binding. Their sequences are 5′-CGGGTTAAAAACCGATGTCACATCGGCCGTTCGAA-3′ (upper strand) and 5′-TTTCGAACGGCCGATGTGACATCGGTTTTTAACCC-3′ (lower strand). The activation profile of hPPARα by CFA is shown in Fig. 1A. This receptor is also activated by other known activators of PPARs, e.g. WY-14,643 and ETYA in HepG2 and CV-1 cells (data not shown). A second human PPAR subtype termed hNUC1 was cloned from a kidney cDNA library. This receptor has 61% homology to hPPARα and the two cysteine residues in the “D” box are separated by three amino acids (E, R, and S, positions 112-114 of the amino acid sequence). This is a characteristic of PPARs(5Dreyer C. Krey G. Hansjorg K. Givel F. Helftenbein G. Wahli W. Cell. 1992; 68: 879-887Abstract Full Text PDF PubMed Scopus (1214) Google Scholar). All the other nuclear receptors have five amino acids in the same region. Therefore, we consider hNUC1 a member of the PPAR family. The hNUC1 receptor, unlike hPPARα is not activated in HepG2 or CV-1 cells by CFA or ETYA (Fig. 1, B and C). The slight activation seen in the absence of transfected receptor is presumably due to the endogenous PPARs in the cell line utilized. Transfected hNUC1 did however decrease the response from the endogenous PPARs. This suggested that hNUC1 may act as a repressor of hPPAR function. Therefore, to demonstrate repression of hPPARα activity by hNUC1, we co-transfected increasing amounts of hNUC1 plasmid with a constant amount of hPPARα expressing plasmid. We saw a strong dose dependent repression of hPPARα activity by hNUC1 (Fig. 2A). Complete repression was observed with 0.1 μg of cotransfected hNUC1 plasmid. Repression by hNUC1 was also observed on rat PPARα and on hPPARα in the presence of ETYA, WY-14,643, and other fibrates (data not shown). To determine whether hNUC1 also represses activation of hPPARα on the natural acyl-CoA oxidase gene promoter, we performed co-transfection assays with the AOX-LUC reporter (Fig. 2B). We observe activation of hPPARα from the AOX promoter in the presence of WY-14,643. Co-transfected hNUC1 completely blocks this activation. No activation was observed by hNUC1 itself in the presence or absence of WY-14,643. We conclude that hNUC1 can repress hPPARα activation through the AOX promoter. We next determined the specificity of hNUC1 repression. We tested the effect of hNUC1 on other members of the steroid receptor family (Fig. 3, A-D). Activation of hTRβ by LT3 through a palindromic TRE was repressed by 65% by hNUC1 (Fig. 3A). Repression increased to 75% in the presence of CFA. However, many TR inducible genes contain TREs that involve direct repeats of the 5′-AGGTCA-3′ motif. We therefore tested whether hNUC1 could also repress activation of hTRβ through a DR4 motif(26Umsono K. Murakami K.K. Thompson C.C. Evans R.M. Cell. 1991; 65: 1255-1266Abstract Full Text PDF PubMed Scopus (1497) Google Scholar). We observe repression of TR activation through a DR4 element by hNUC1 in the absence and presence of CFA (Fig. 3B). Repression was also observed with hTRα, although to a lesser degree (data not shown). To determine whether hNUC1 could repress activation of other members of the steroid receptor family, we performed similar assays with the PR and RARα (Fig. 3, C and D). With 0.1 μg of transfected hNUC1 plasmid no repression of PR activity was observed. Similarly with RARα no significant repression by hNUC1 in the absence of CFA was observed. With CFA, 50% repression of RARα activity was observed (Fig. 3D). At higher levels of transfected hNUC1 (0.5 μg) we observe a modest stimulation of activity (Fig. 3, C and D). CFA reduces this induction. However, this stimulation was not observed with hPPARα and 0.5 μg of co-transfected hNUC1 (Fig. 2A). This result indicates that even at high levels of hNUC1, no repression of PR or RARα is observed. Further, hNUC1 did not repress the activity of the estrogen receptor through an estrogen-responsive promoter (data not shown). We conclude that hNUC1 is not a general transcriptional repressor. Among the receptors tested, it strongly repressed activation of hPPARα and hTR. Repression occurred in the absence of clofibric acid, but was enhanced in its presence. One mechanism by which hNUC1 could repress activation by hPPARα is by binding to the PPRE. To demonstrate binding of hNUC1 to a PPRE, we performed gel retardation assays. With hNUC1 or hRXRα alone, very weak retarded complexes are seen (Fig. 4A, lanes 1 and 4). Addition of RXRα enhances binding of hNUC1 (lane 2) demonstrating cooperative binding of hNUC1 and hRXRα to the PPRE. The specific complex is not observed in control reactions using Sf21 and unprogrammed reticulocyte lysate (lanes 3, 5, and 6), nor with a probe with an unrelated sequence (lane 7). Co-operative binding to the PPRE was also observed between hNUC1 and hRXRα and between hPPARα and hRXRα in gel retardation assays using whole cell extracts from COS cells transfected with the respective expression plasmids (data not shown). These experiments also suggested that transfected hPPARα and hNUC1 were expressed at roughly equal levels as judged by the retarded band intensities. Therefore, to account for the almost complete inhibition of hPPARα induced response at 1:1 ratio of hNUC1 to hPPARα plasmid DNA, the affinity of the hNUC1-RXR complex for the PPRE must be significantly higher than that of hPPARα. Fig. 4B shows the result of a competition experiment using increasing amounts of unlabeled PPRE or probes with unrelated sequences. The hNUC1-RXR-PPRE complex is specific since the unrelated oligonucleotides (lanes 14-18) compete very poorly compared to the specific PPRE containing oligonucleotides (lanes 8-12). It also has a higher mobility than the hPPARα-RXR-PPRE complex. The relative affinity of hNUC1-hRXRα for the PPRE is comparable to that of hPPAR-hRXRα (compare lanes 1-6 with lanes 7-12). Given that the expression levels of hNUC1 and hPPARα in transfected cells and their affinities for the PPRE are similar, competition for PPRE alone cannot wholly account for the strong repression of hPPARα activity by hNUC1. We therefore investigated whether hNUC1 could be titrating a limiting factor required for hPPARα activity. To investigate this possibility, we performed an experiment where we systematically altered the ratio of activator to repressor (Fig. 5). If hNUC1 was indeed titrating out a limiting factor, one would predict from simple equilibrium considerations that increasing the amount of activator (hPPARα) would overcome the repression. We observe that increasing the ratio of hPPARα to hNUC1 overcame the repression by hNUC1. The activation observed with 0.25 and 0.5 μg of hPPARα in the presence of 0.05 μg of hNUC is the same as that observed in the absence of hNUC. Therefore, at sufficiently high ratios of activator to repressor (5- and 10-fold), repression by hNUC was completely overcome. This data is consistent with the hypothesis that hNUC represses hPPARα by titrating a limiting factor required for hPPARα activation. We cannot rigorously rule out the possibility of competitive DNA binding by hNUC1. This is however unlikely since hNUC1 and hPPARα have similar affinities for the PPRE in presence of excess RXR (Fig. 4). This factor is probably not utilized by all receptors since hNUC1 does not have a pronounced repressive effect on the PR and RAR. We have cloned a subtype of the human PPAR family, hNUC1. The sequence of our clone is similar to the previously published sequence (8Schmidt A. Endo N. Rutledge S.J. Vogel R. Shinar D. Rodan G.A. Mol. Endocrinol. 1992; 6: 1634-1641Crossref PubMed Scopus (366) Google Scholar) except for alanine at position 292 of the amino acid sequence instead of proline. Among the Xenopus PPAR subtypes, xPPARβ has the closest homology to hNUC1. It is possible that hNUC1 is the human homolog of xPPARβ. Although hNUC1 is a member of the PPAR family, we have shown that hNUC1 is not transcriptionally activated by compounds that normally activate hPPARα through the PPRE identified in the acyl-coenzyme A oxidase gene. This has also been observed by Schmidt et al.(8Schmidt A. Endo N. Rutledge S.J. Vogel R. Shinar D. Rodan G.A. Mol. Endocrinol. 1992; 6: 1634-1641Crossref PubMed Scopus (366) Google Scholar) with hNUC1 and certain fatty acids. We further demonstrate that hNUC1 is a dominant negative repressor of hPPARα and hTR. Several mechanisms of repression can be suggested. First, the mechanism of repression by hNUC1 could be similar to the repression of thyroid hormone action by the non-hormone binding rat erbA-α2(19Koenig R.J. Lazar M.A. Hodin R.A. Brent G.A. Larsen P.R. Chin W.W. Moore D.D. Nature. 1989; 337: 659-661Crossref PubMed Scopus (351) Google Scholar). However, Schmidt et al.(8Schmidt A. Endo N. Rutledge S.J. Vogel R. Shinar D. Rodan G.A. Mol. Endocrinol. 1992; 6: 1634-1641Crossref PubMed Scopus (366) Google Scholar) have demonstrated that a chimera of the N terminus including the DNA binding domain of the GR fused to the ligand binding domain of hNUC1 (GR-NUC) was activated by WY-14,643. This suggests that hNUC1 can bind the as yet unidentified “ligand” for PPAR. Interestingly, a similar estrogen receptor-NUC chimera was not activated by WY-14,643. This suggests that there is probably no WY-14,643 inducible transcriptional activation function in the ligand binding domain of hNUC1 and further that the activation observed with the GR-NUC chimera was from the strong activation function in the N terminus of the GR(20Godowski P.J. Picard D. Yamamoto K.R. Science. 1988; 241: 812-816Crossref PubMed Scopus (167) Google Scholar, 21Hollenberg S.M. Evans R.M. Cell. 1988; 55: 899-906Abstract Full Text PDF PubMed Scopus (549) Google Scholar). Secondly, hNUC1 could be binding to the PPRE thereby antagonizing activation of hPPARα. COUP-TF has been shown to inhibit PPAR activation by a similar mechanism(22Miyata K.S. Zhang B. Marcus S.L. Capone J.P. Rachubinski R.A. J. Biol. Chem. 1993; 268: 19169-19172Abstract Full Text PDF PubMed Google Scholar). We have demonstrated cooperative binding of hNUC1 and hRXRα to a PPRE. In the absence of a CFA inducible transcription activation function of hNUC1, this mechanism could explain the repression of hPPARα activity by hNUC1. However, since the affinity of the hNUC1-RXR complex for the PPRE is comparable to that of hPPARα-RXR, this cannot wholly explain the strong repression observed with hNUC1. Finally we show that repression by hNUC1 can be reversed by excess transfected hPPARα. This suggests competition for a limiting factor required for transcriptional activity of hPPARα. How hNUC1 represses TR activity is not clear at present. One possibility is the formation of transcriptionally inactive heterodimers as in the case of helix loop helix proteins(23Benezra R. Davis R.L. Lockshon D. Turner D.L. Weintraub H. Cell. 1990; 61: 49-59Abstract Full Text PDF PubMed Scopus (1804) Google Scholar). Heterodimerization between rPPAR and TR has recently been demonstrated(24Bogazzi F. Hudson L.D. Nikodem V.M. J. Biol. Chem. 1994; 269: 11683-11686Abstract Full Text PDF PubMed Google Scholar). The role of CFA on hNUC1-mediated repression is also unclear at present. This is the first demonstration of repression by one PPAR subtype on another and on TR. Our data and that of others (25Hertz R. Kalderon B. Bar-Tana J. Biochemie (Paris). 1993; 75: 257-261Crossref PubMed Scopus (14) Google Scholar) suggest a convergence of the thyroid hormone- and peroxisome- mediated fatty acid metabolism pathways. Overcoming repression by hNUC1 may be a way to increase activity of PPARs and thyroid hormone receptors. We acknowledge the contribution of Dan Noonan in the cloning of hNUC1. We thank Donald McDonnell, Jon Rosen, and Jeff Miner for very helpful discussions and critically reading the manuscript, Rich Heyman and Dave Clemm for the hRXRα protein extract, and our colleagues in the Molecular Biology, Cell Biology, and the New Leads Discovery Department for their help. We thank Glaxo Research and Development Ltd. UK for helpful discussions and support. Note Added in Proof-While this manuscript was under review, repression of mouse PPARα by mouse NUC1 was demonstrated (Kleiwer, S. A., Forman, B. M., Blumberg, B., Ong, E. S., Borgmeyer, U., Mangelsdorf, D. J., Umesono, K., and Evans, R. M.(1994) Proc. Natl. Acad. Sci. U. S. A.91, 7355-7359)." @default.
• W2023697788 created "2016-06-24" @default.
• W2023697788 creator A5041360491 @default.
• W2023697788 creator A5078043600 @default.
• W2023697788 date "1995-02-01" @default.
• W2023697788 modified "2023-10-16" @default.
• W2023697788 title "The Human Peroxisome Proliferator-activated Receptor (PPAR) Subtype NUC1 Represses the Activation of hPPARα and Thyroid Hormone Receptors" @default.
• W2023697788 cites W1548019355 @default.
• W2023697788 cites W1595020114 @default.
• W2023697788 cites W1596666097 @default.
• W2023697788 cites W1971263640 @default.
• W2023697788 cites W1976976178 @default.
• W2023697788 cites W1978125779 @default.
• W2023697788 cites W1979761686 @default.
• W2023697788 cites W1991050074 @default.
• W2023697788 cites W1997473658 @default.
• W2023697788 cites W1999624815 @default.
• W2023697788 cites W2003960793 @default.
• W2023697788 cites W2005914718 @default.
• W2023697788 cites W2010234214 @default.
• W2023697788 cites W2011467252 @default.
• W2023697788 cites W2018815974 @default.
• W2023697788 cites W2037961015 @default.
• W2023697788 cites W2066092624 @default.
• W2023697788 cites W2068669347 @default.
• W2023697788 cites W2072233737 @default.
• W2023697788 cites W2075245841 @default.
• W2023697788 cites W2089264059 @default.
• W2023697788 cites W2116470680 @default.
• W2023697788 cites W2129972061 @default.
• W2023697788 cites W2159511823 @default.
• W2023697788 cites W2180717168 @default.
• W2023697788 doi "https://doi.org/10.1074/jbc.270.8.3836" @default.
• W2023697788 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/7876127" @default.
• W2023697788 hasPublicationYear "1995" @default.
• W2023697788 type Work @default.
• W2023697788 sameAs 2023697788 @default.
• W2023697788 citedByCount "84" @default.
• W2023697788 countsByYear W20236977882012 @default.
• W2023697788 countsByYear W20236977882013 @default.
• W2023697788 countsByYear W20236977882014 @default.
• W2023697788 countsByYear W20236977882016 @default.
• W2023697788 countsByYear W20236977882019 @default.
• W2023697788 crossrefType "journal-article" @default.
• W2023697788 hasAuthorship W2023697788A5041360491 @default.
• W2023697788 hasAuthorship W2023697788A5078043600 @default.
• W2023697788 hasBestOaLocation W20236977881 @default.
• W2023697788 hasConcept C104317684 @default.
• W2023697788 hasConcept C109115496 @default.
• W2023697788 hasConcept C121608353 @default.
• W2023697788 hasConcept C126322002 @default.
• W2023697788 hasConcept C127078168 @default.
• W2023697788 hasConcept C134018914 @default.
• W2023697788 hasConcept C14093617 @default.
• W2023697788 hasConcept C149574134 @default.
• W2023697788 hasConcept C170493617 @default.
• W2023697788 hasConcept C185592680 @default.
• W2023697788 hasConcept C187345961 @default.
• W2023697788 hasConcept C23589133 @default.
• W2023697788 hasConcept C530470458 @default.
• W2023697788 hasConcept C55493867 @default.
• W2023697788 hasConcept C63932345 @default.
• W2023697788 hasConcept C71315377 @default.
• W2023697788 hasConcept C71924100 @default.
• W2023697788 hasConcept C86339819 @default.
• W2023697788 hasConcept C86803240 @default.
• W2023697788 hasConceptScore W2023697788C104317684 @default.
• W2023697788 hasConceptScore W2023697788C109115496 @default.
• W2023697788 hasConceptScore W2023697788C121608353 @default.
• W2023697788 hasConceptScore W2023697788C126322002 @default.
• W2023697788 hasConceptScore W2023697788C127078168 @default.
• W2023697788 hasConceptScore W2023697788C134018914 @default.
• W2023697788 hasConceptScore W2023697788C14093617 @default.
• W2023697788 hasConceptScore W2023697788C149574134 @default.
• W2023697788 hasConceptScore W2023697788C170493617 @default.
• W2023697788 hasConceptScore W2023697788C185592680 @default.
• W2023697788 hasConceptScore W2023697788C187345961 @default.
• W2023697788 hasConceptScore W2023697788C23589133 @default.
• W2023697788 hasConceptScore W2023697788C530470458 @default.
• W2023697788 hasConceptScore W2023697788C55493867 @default.
• W2023697788 hasConceptScore W2023697788C63932345 @default.
• W2023697788 hasConceptScore W2023697788C71315377 @default.
• W2023697788 hasConceptScore W2023697788C71924100 @default.
• W2023697788 hasConceptScore W2023697788C86339819 @default.
• W2023697788 hasConceptScore W2023697788C86803240 @default.
• W2023697788 hasIssue "8" @default.
• W2023697788 hasLocation W20236977881 @default.
• W2023697788 hasOpenAccess W2023697788 @default.
• W2023697788 hasPrimaryLocation W20236977881 @default.
• W2023697788 hasRelatedWork W1984522924 @default.
• W2023697788 hasRelatedWork W1989567929 @default.
• W2023697788 hasRelatedWork W2023697788 @default.
• W2023697788 hasRelatedWork W2063059112 @default.
• W2023697788 hasRelatedWork W2077631485 @default.
• W2023697788 hasRelatedWork W2096799980 @default.
• W2023697788 hasRelatedWork W2116117474 @default.
• W2023697788 hasRelatedWork W2142860743 @default.
• W2023697788 hasRelatedWork W90907977 @default.

• next