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Center for Biotechnology Department of Biosciences Karolinska Institute Novum, S-14157 Huddinge, Sweden
Transcriptional regulation of gene expression by
nuclear receptors requires negatively and positively acting cofactors.
Recent models for receptor activation propose that certain receptors in
the absence of ligands can recruit corepressors while ligand binding
results in conformational changes leading to the recruitment of
coactivators. Previous work has established a coactivator role for the
SRC-1 family members as well as an involvement of the coactivators
CBP/p300 in nuclear receptor signaling. However, in addition to
coactivators, ligand-activated nuclear receptors bind a number of
different proteins that possibly serve other functions. Using
peroxisome proliferator-activated receptor-
(PPAR) as bait in a
yeast two-hybrid screening, we have isolated nuclear factor RIP140
whose function in receptor activation is unclear. We now report a
detailed characterization of RIP140 action with a focus on the retinoid
X receptor (RXR) heterodimeric receptors PPAR and thyroid hormone
receptor (TR). We show that putative PPAR ligands enhance the
interaction of RIP140 with the rat PPAR subtypes and 
in
solution but not with PPAR/RXR heterodimers on DNA. However, RIP140
forms ternary complexes in the presence of RXR ligands. Similar
experiments with TR support the high affinity of RIP140 to the RXR
subunit and also suggest that either partner in the TR/RXR heterodimer
can independently respond to ligand. Coactivation experiments in yeast
and mammalian cells confirm the coactivator role for SRC-1, but not for
RIP140. We provide important evidence that the in vitro
binding of RIP140 and SRC-1 to nuclear receptors is competitive. Since
RIP140 generally down-regulates receptor activity in mammalian cells
and specifically down-regulates coactivation mediated by SRC-1, we
propose a model in which RIP140 indirectly regulates nuclear receptor
AF-2 activity by competition for coactivators such as SRC-1.
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E. M. Resnick, D. A. Schreihofer, A. Periasamy, and M. A. Shupnik Truncated Estrogen Receptor Product-1 Suppresses Estrogen Receptor Transactivation by Dimerization with Estrogen Receptors alpha and beta J. Biol. Chem., March 15, 2000; 275(10): 7158 - 7166. [Abstract] [Full Text] [PDF]
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D. Robyr, A. P. Wolffe, and W. Wahli Nuclear Hormone Receptor Coregulators In Action: Diversity For Shared Tasks Mol. Endocrinol., March 1, 2000; 14(3): 329 - 347. [Full Text]
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F. Caira, P. Antonson, M. Pelto-Huikko, E. Treuter, and J.-A. Gustafsson Cloning and Characterization of RAP250, a Novel Nuclear Receptor Coactivator J. Biol. Chem., February 25, 2000; 275(8): 5308 - 5317. [Abstract] [Full Text] [PDF]
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L. Johansson, A. Båvner, J. S. Thomsen, M. Färnegårdh, J.-A. Gustafsson, and E. Treuter The Orphan Nuclear Receptor SHP Utilizes Conserved LXXLL-Related Motifs for Interactions with Ligand-Activated Estrogen Receptors Mol. Cell. Biol., February 15, 2000; 20(4): 1124 - 1133. [Abstract] [Full Text]
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J. An, R. C. J. Ribeiro, P. Webb, J.-A. Gustafsson, P. J. Kushner, J. D. Baxter, and D. C. Leitman Estradiol repression of tumor necrosis factor-alpha transcription requires estrogen receptor activation function-2 and is enhanced by coactivators PNAS, December 21, 1999; 96(26): 15161 - 15166. [Abstract] [Full Text] [PDF]
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C. L. Bevan, S. Hoare, F. Claessens, D. M. Heery, and M. G. Parker The AF1 and AF2 Domains of the Androgen Receptor Interact with Distinct Regions of SRC1 Mol. Cell. Biol., December 1, 1999; 19(12): 8383 - 8392. [Abstract] [Full Text] [PDF]
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P. Delerive, K. De Bosscher, S. Besnard, W. Vanden Berghe, J. M. Peters, F. J. Gonzalez, J.-C. Fruchart, A. Tedgui, G. Haegeman, and B. Staels Peroxisome Proliferator-activated Receptor alpha Negatively Regulates the Vascular Inflammatory Gene Response by Negative Cross-talk with Transcription Factors NF-kappa B and AP-1 J. Biol. Chem., November 5, 1999; 274(45): 32048 - 32054. [Abstract] [Full Text] [PDF]
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C.-H. Lee and L.-N. Wei Characterization of Receptor-interacting Protein 140 in Retinoid Receptor Activities J. Biol. Chem., October 29, 1999; 274(44): 31320 - 31326. [Abstract] [Full Text] [PDF]
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B. Desvergne and W. Wahli Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism Endocr. Rev., October 1, 1999; 20(5): 649 - 688. [Abstract] [Full Text]
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M. B. Kumar, R. W. Tarpey, and G. H. Perdew Differential Recruitment of Coactivator RIP140 by Ah and Estrogen Receptors. ABSENCE OF A ROLE FOR LXXLL MOTIFS J. Biol. Chem., August 6, 1999; 274(32): 22155 - 22164. [Abstract] [Full Text] [PDF]
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F. F. Wiebel, K. R. Steffensen, E. Treuter, D. Feltkamp, and J.-A. Gustafsson Ligand-Independent Coregulator Recruitment by the Triply Activatable OR1/Retinoid X Receptor-{alpha} Nuclear Receptor Heterodimer Mol. Endocrinol., July 1, 1999; 13(7): 1105 - 1118. [Abstract] [Full Text]
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N. Subramaniam, E. Treuter, and S. Okret Receptor Interacting Protein RIP140 Inhibits Both Positive and Negative Gene Regulation by Glucocorticoids J. Biol. Chem., June 18, 1999; 274(25): 18121 - 18127. [Abstract] [Full Text] [PDF]
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G. N. Lopez, P. Webb, J. H. Shinsako, J. D. Baxter, G. L. Greene, and P. J. Kushner Titration by Estrogen Receptor Activation Function-2 of Targets That Are Downstream from Coactivators Mol. Endocrinol., June 1, 1999; 13(6): 897 - 909. [Abstract] [Full Text]
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F. Schaufele Regulation of Estrogen Receptor Activation of the Prolactin Enhancer/Promoter by Antagonistic Activation Function-2-Interacting Proteins Mol. Endocrinol., June 1, 1999; 13(6): 935 - 945. [Abstract] [Full Text]
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L. Gelman, G. Zhou, L. Fajas, E. Raspe, J.-C. Fruchart, and J. Auwerx p300 Interacts with the N- and C-terminal Part of PPARgamma 2 in a Ligand-independent and -dependent Manner, Respectively J. Biol. Chem., March 19, 1999; 274(12): 7681 - 7688. [Abstract] [Full Text] [PDF]
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E. Treuter, L. Johansson, J. S. Thomsen, A. Warnmark, J. Leers, M. Pelto-Huikko, M. Sjoberg, A. P. H. Wright, G. Spyrou, and J.-A. Gustafsson Competition between Thyroid Hormone Receptor-associated Protein (TRAP) 220 and Transcriptional Intermediary Factor (TIF) 2 for Binding to Nuclear Receptors. IMPLICATIONS FOR THE RECRUITMENT OF TRAP AND p160 COACTIVATOR COMPLEXES J. Biol. Chem., March 5, 1999; 274(10): 6667 - 6677. [Abstract] [Full Text] [PDF]
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G. A. Peters and S. A. Khan Estrogen Receptor Domains E and F: Role in Dimerization and Interaction with Coactivator RIP-140 Mol. Endocrinol., February 1, 1999; 13(2): 286 - 296. [Abstract] [Full Text]
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D. A. Schreihofer, E. M. Resnick, A. Y. Soh, and M. A. Shupnik Transcriptional Regulation by a Naturally Occurring Truncated Rat Estrogen Receptor (ER), Truncated ER Product-1 (TERP-1) Mol. Endocrinol., February 1, 1999; 13(2): 320 - 329. [Abstract] [Full Text]
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Y.-C. Zhou and D. J. Waxman Cross-talk between Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) and Peroxisome Proliferator-activated Receptor-alpha (PPARalpha ) Signaling Pathways. GROWTH HORMONE INHIBITION OF PPARalpha TRANSCRIPTIONAL ACTIVITY MEDIATED BY STAT5b J. Biol. Chem., January 29, 1999; 274(5): 2672 - 2681. [Abstract] [Full Text] [PDF]
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 E Remboutsika, Y Lutz, A Gansmuller, J. Vonesch, R Losson, and P Chambon The putative nuclear receptor mediator TIF1alpha is tightly associated with euchromatin J. Cell Sci., January 6, 1999; 112(11): 1671 - 1683. [Abstract] [PDF]
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L. Johansson, J. S. Thomsen, A. E. Damdimopoulos, G. Spyrou, J.-A. Gustafsson, and E. Treuter The Orphan Nuclear Receptor SHP Inhibits Agonist-dependent Transcriptional Activity of Estrogen Receptors ERalpha and ERbeta J. Biol. Chem., January 1, 1999; 274(1): 345 - 353. [Abstract] [Full Text] [PDF]
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P. Alen, F. Claessens, E. Schoenmakers, J. V. Swinnen, G. Verhoeven, W. Rombauts, and B. Peeters Interaction of the Putative Androgen Receptor-Specific Coactivator ARA70/ELE1{alpha} with Multiple Steroid Receptors and Identification of an Internally Deleted ELE1{beta} Isoform Mol. Endocrinol., January 1, 1999; 13(1): 117 - 128. [Abstract] [Full Text]
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C.-H. Lee, C. Chinpaisal, and L.-N. Wei Cloning and Characterization of Mouse RIP140, a Corepressor for Nuclear Orphan Receptor TR2 Mol. Cell. Biol., November 1, 1998; 18(11): 6745 - 6755. [Abstract] [Full Text]
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J. Leers, E. Treuter, and J.-A. Gustafsson Mechanistic Principles in NR Box-Dependent Interaction between Nuclear Hormone Receptors and the Coactivator TIF2 Mol. Cell. Biol., October 1, 1998; 18(10): 6001 - 6013. [Abstract] [Full Text]
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H. Zhang, J. S. Thomsen, L. Johansson, J.-A. Gustafsson, and E. Treuter DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors J. Biol. Chem., December 15, 2000; 275(51): 39855 - 39859. [Abstract] [Full Text] [PDF]
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Z. Yan and A. M. Jetten Characterization of the Repressor Function of the Nuclear Orphan Receptor Retinoid Receptor-related Testis-associated Receptor/Germ Cell Nuclear Factor J. Biol. Chem., November 3, 2000; 275(45): 35077 - 35085. [Abstract] [Full Text] [PDF]
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A. Warnmark, T. Almlof, J. Leers, J.-A. Gustafsson, and E. Treuter Differential Recruitment of the Mammalian Mediator Subunit TRAP220 by Estrogen Receptors ERalpha and ERbeta J. Biol. Chem., June 22, 2001; 276(26): 23397 - 23404. [Abstract] [Full Text] [PDF]
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M. Elholm, I. Dam, C. Jorgensen, A.-M. Krogsdam, D. Holst, I. Kratchmarova, M. Gottlicher, J.-A. Gustafsson, R. Berge, T. Flatmark, et al. Acyl-CoA Esters Antagonize the Effects of Ligands on Peroxisome Proliferator-activated Receptor alpha Conformation, DNA Binding, and Interaction with Co-factors J. Biol. Chem., June 8, 2001; 276(24): 21410 - 21416. [Abstract] [Full Text] [PDF]
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