JBC GenomeOne product landing page

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.M200743200 on March 4, 2002

J. Biol. Chem., Vol. 277, Issue 22, 19649-19657, May 31, 2002
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
277/22/19649    most recent
M200743200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, G.
Right arrow Articles by Li, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, G.
Right arrow Articles by Li, Y.

T0070907, a Selective Ligand for Peroxisome Proliferator-activated Receptor gamma , Functions as an Antagonist of Biochemical and Cellular Activities*

Gary Lee, Fabienne Elwood, John McNally, Jennifer Weiszmann, Michelle Lindstrom, Kate Amaral, Motonao Nakamura, Shichang Miao, Ping Cao, R. Marc Learned, Jin-Long Chen, and Yang LiDagger

From Tularik Inc., South San Francisco, California 94080

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma  (PPARgamma (NR1C3)) plays a central role in adipogenesis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. In a search for novel non-TZD ligands for PPARgamma , T0070907 was identified as a potent and selective PPARgamma antagonist. With an apparent binding affinity (concentration at 50% inhibition of [3H]rosiglitazone binding or IC50) of 1 nM, T0070907 covalently modifies PPARgamma on cysteine 313 in helix 3 of human PPARgamma 2. T0070907 blocked PPARgamma function in both cell-based reporter gene and adipocyte differentiation assays. Consistent with its role as an antagonist of PPARgamma , T0070907 blocked agonist-induced recruitment of coactivator-derived peptides to PPARgamma in a homogeneous time-resolved fluorescence-based assay and promoted recruitment of the transcriptional corepressor NCoR to PPARgamma in both glutathione S-transferase pull-down assays and a PPARgamma /retinoid X receptor (RXR) alpha -dependent gel shift assay. Studies with mutant receptors suggest that T0070907 modulates the interaction of PPARgamma with these cofactor proteins by affecting the conformation of helix 12 of the PPARgamma ligand-binding domain. Interestingly, whereas the T0070907-induced NCoR recruitment to PPARgamma /RXRalpha heterodimer can be almost completely reversed by the simultaneous treatment with RXRalpha agonist LGD1069, T0070907 treatment has only modest effects on LGD1069-induced coactivator recruitment to the PPARgamma /RXRalpha heterodimer. These results suggest that the activity of PPARgamma antagonists can be modulated by the availability and concentration of RXR agonists. T0070907 is a novel tool for the study of PPARgamma /RXRalpha heterodimer function.

* 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.

Dagger To whom correspondence should be addressed: Tularik Inc., Two Corporate Dr., South San Francisco, CA 94080. Tel.: 650-825-7524; Fax: 650-825-7400; E-mail: yli@tularik.com.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


This article has been cited by other articles:


Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
K. Takahashi, S. Yamaguchi, T. Shimoyama, H. Seki, K. Miyokawa, H. Katsuta, T. Tanaka, K. Yoshimoto, H. Ohno, S. Nagamatsu, et al.
JNK- and I{kappa}B-dependent pathways regulate MCP-1 but not adiponectin release from artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate in vitro
Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E898 - E909.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Li, Z. Wang, N. Furukawa, P. Escaron, J. Weiszmann, G. Lee, M. Lindstrom, J. Liu, X. Liu, H. Xu, et al.
T2384, a Novel Antidiabetic Agent with Unique Peroxisome Proliferator-activated Receptor {gamma} Binding Properties
J. Biol. Chem., April 4, 2008; 283(14): 9168 - 9176.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
H. Ge, J. Weiszmann, J. D. Reagan, J. Gupte, H. Baribault, T. Gyuris, J.-L. Chen, H. Tian, and Y. Li
Elucidation of signaling and functional activities of an orphan GPCR, GPR81
J. Lipid Res., April 1, 2008; 49(4): 797 - 803.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
S. Handeli and J. A. Simon
A small-molecule inhibitor of Tcf/{beta}-catenin signaling down-regulates PPAR{gamma} and PPAR{delta} activities
Mol. Cancer Ther., March 1, 2008; 7(3): 521 - 529.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
Y. Bren-Mattison, A. M. Meyer, V. Van Putten, H. Li, K. Kuhn, R. Stearman, M. Weiser-Evans, R. A. Winn, L. E. Heasley, and R. A. Nemenoff
Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor-{gamma} in Non-Small-Cell Lung Cancer Cells Are Mediated by Suppression of Cyclooxygenase-2 via Inhibition of Nuclear Factor-{kappa}B
Mol. Pharmacol., March 1, 2008; 73(3): 709 - 717.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
S. Chintharlapalli, S. Papineni, S. Liu, I. Jutooru, G. Chadalapaka, S.-d. Cho, R. S. Murthy, Y. You, and S. Safe
2-Cyano-lup-1-en-3-oxo-20-oic acid, a cyano derivative of betulinic acid, activates peroxisome proliferator-activated receptor {gamma} in colon and pancreatic cancer cells
Carcinogenesis, November 1, 2007; 28(11): 2337 - 2346.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Xu, S. R. Farmer, and B. D. Smith
Peroxisome Proliferator-activated Receptor {gamma} Interacts with CIITA{middle dot}RFX5 Complex to Repress Type I Collagen Gene Expression
J. Biol. Chem., September 7, 2007; 282(36): 26046 - 26056.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
B. Askari, J. E. Kanter, A. M. Sherrid, D. L. Golej, A. T. Bender, J. Liu, W. A. Hsueh, J. A. Beavo, R. A. Coleman, and K. E. Bornfeldt
Rosiglitazone Inhibits Acyl-CoA Synthetase Activity and Fatty Acid Partitioning to Diacylglycerol and Triacylglycerol via a Peroxisome Proliferator-Activated Receptor-{gamma}-Independent Mechanism in Human Arterial Smooth Muscle Cells and Macrophages
Diabetes, April 1, 2007; 56(4): 1143 - 1152.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
S. Folkertsma, P. I. van Noort, A. de Heer, P. Carati, R. Brandt, A. Visser, G. Vriend, and J. de Vlieg
The Use of in Vitro Peptide Binding Profiles and in Silico Ligand-Receptor Interaction Profiles to Describe Ligand-Induced Conformations of the Retinoid X Receptor {alpha} Ligand-Binding Domain
Mol. Endocrinol., January 1, 2007; 21(1): 30 - 48.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
D. M. Ray, F. Akbiyik, and R. P. Phipps
The Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Ligands 15-Deoxy-{Delta}12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPAR{gamma}-Independent Mechanisms
J. Immunol., October 15, 2006; 177(8): 5068 - 5076.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Zuo, L. Qiang, and S. R. Farmer
Activation of CCAAT/Enhancer-binding Protein (C/EBP) {alpha} Expression by C/EBPbeta during Adipogenesis Requires a Peroxisome Proliferator-activated Receptor-{gamma}-associated Repression of HDAC1 at the C/ebp{alpha} Gene Promoter
J. Biol. Chem., March 24, 2006; 281(12): 7960 - 7967.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
I. Bogacka, B. Ukropcova, M. McNeil, J. M. Gimble, and S. R. Smith
Structural and Functional Consequences of Mitochondrial Biogenesis in Human Adipocytes in Vitro
J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6650 - 6656.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Fukuen, M. Iwaki, A. Yasui, M. Makishima, M. Matsuda, and I. Shimomura
Sulfonylurea Agents Exhibit Peroxisome Proliferator-activated Receptor {gamma} Agonistic Activity
J. Biol. Chem., June 24, 2005; 280(25): 23653 - 23659.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
J. M. Wallace, M. Schwarz, P. Coward, J. Houze, J. K. Sawyer, K. L. Kelley, A. Chai, and L. L. Rudel
Effects of peroxisome proliferator-activated receptor {alpha}/{delta} agonists on HDL-cholesterol in vervet monkeys
J. Lipid Res., May 1, 2005; 46(5): 1009 - 1016.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Shiraki, N. Kamiya, S. Shiki, T. S. Kodama, A. Kakizuka, and H. Jingami
{alpha},{beta}-Unsaturated Ketone Is a Core Moiety of Natural Ligands for Covalent Binding to Peroxisome Proliferator-activated Receptor {gamma}
J. Biol. Chem., April 8, 2005; 280(14): 14145 - 14153.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
R. Contractor, I. J. Samudio, Z. Estrov, D. Harris, J. A. McCubrey, S. H. Safe, M. Andreeff, and M. Konopleva
A Novel Ring-Substituted Diindolylmethane,1,1-Bis[3'-(5-Methoxyindolyl)]-1-(p-t-Butylphenyl) Methane, Inhibits Extracellular Signal-Regulated Kinase Activation and Induces Apoptosis in Acute Myelogenous Leukemia
Cancer Res., April 1, 2005; 65(7): 2890 - 2898.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
H.-P. Guan, T. Ishizuka, P. C. Chui, M. Lehrke, and M. A. Lazar
Corepressors selectively control the transcriptional activity of PPAR{gamma} in adipocytes
Genes & Dev., February 15, 2005; 19(4): 453 - 461.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
C. Knouff and J. Auwerx
Peroxisome Proliferator-Activated Receptor-{gamma} Calls for Activation in Moderation: Lessons from Genetics and Pharmacology
Endocr. Rev., December 1, 2004; 25(6): 899 - 918.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Hong, I. Samudio, S. Liu, M. Abdelrahim, and S. Safe
Peroxisome Proliferator-Activated Receptor {gamma}-Dependent Activation of p21 in Panc-28 Pancreatic Cancer Cells Involves Sp1 and Sp4 Proteins
Endocrinology, December 1, 2004; 145(12): 5774 - 5785.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
F. J. Sanchez-Gomez, E. Cernuda-Morollon, K. Stamatakis, and D. Perez-Sala
Protein Thiol Modification by 15-deoxy-{Delta}12,14-Prostaglandin J2 Addition in Mesangial Cells: Role in the Inhibition of Pro-inflammatory Genes
Mol. Pharmacol., November 1, 2004; 66(5): 1349 - 1358.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Liu, C.-K. Shaw, E. L. Reineke, Y. Liu, and H.-Y. Kao
Retinoid X Receptor {alpha} (RXR{alpha}) Helix 12 Plays an Inhibitory Role in the Recruitment of the p160 Co-activators by Unliganded RXR{alpha}/Retinoic Acid Receptor {alpha} Heterodimers
J. Biol. Chem., October 22, 2004; 279(43): 45208 - 45218.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
M. Konopleva, E. Elstner, T. J. McQueen, T. Tsao, A. Sudarikov, W. Hu, W. D. Schober, R.-Y. Wang, D. Chism, S. M. Kornblau, et al.
Peroxisome proliferator-activated receptor {gamma} and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias
Mol. Cancer Ther., October 1, 2004; 3(10): 1249 - 1262.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
C. Qin, D. Morrow, J. Stewart, K. Spencer, W. Porter, R. Smith III, T. Phillips, M. Abdelrahim, I. Samudio, and S. Safe
A new class of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists that inhibit growth of breast cancer cells: 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes
Mol. Cancer Ther., March 1, 2004; 3(3): 247 - 260.
[Abstract] [Full Text]

Home page
 Mol. Cell. Biol.Home page
B. Farboud, H. Hauksdottir, Y. Wu, and M. L. Privalsky
Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors {beta} and {gamma} Interferes with Corepressor Recruitment and Prevents Transcriptional Repression
Mol. Cell. Biol., April 15, 2003; 23(8): 2844 - 2858.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.