This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wiebel, F. F. Articles by Gustafsson, J.-A. Search for Related Content PubMed PubMed Citation Articles by Wiebel, F. F. Articles by Gustafsson, J.-A.

Ligand-Independent Coregulator Recruitment by the Triply Activatable OR1/Retinoid X Receptor- Nuclear Receptor Heterodimer

Center for Biotechnology (F.F.W., K.R.S., E.T., D.F.) Department of Biosciences Karolinska Institute NOVUM, S-141 57 Huddinge, Sweden
Department of Medical Nutrition (J.-A.G.) Karolinska Institute F-60 NOVUM, S-141 86 Huddinge, Sweden

OR1 is a member of the superfamily of steroid/thyroid hormone nuclear receptors and recognizes DNA as a heterodimer with the 9-cis-retinoic acid receptor RXR (retinoid X receptor). The heterodimeric complex has been shown to be transcriptionally activatable by the RXR ligand as well as certain oxysterols via OR1, but to date uniquely also by heterodimerization itself. Recent studies on other members of the superfamily of nuclear receptors have led to the identification of a number of nuclear receptor-interacting proteins that mediate their regulatory effects on transcription. Here, we address the question of involvement of some of these cofactors in the three modes of activation by the OR1/RXR complex. We show that in vitro the steroid receptor coactivator SRC-1 can be recruited by RXR upon addition of its ligand, and to OR1 upon addition of 22(R)-OH-cholesterol, demonstrating that the latter can act as a direct ligand to OR1. Additionally, heterodimerization is sufficient to recruit SRC-1 to OR1/RXR, indicating SRC-1 as a molecular mediator of dimerization-induced activation. In transfection experiments, coexpression of a nuclear receptor-interacting fragment of SRC-1 abolishes constitutive activation by OR1/RXR, which can be restored by overexpression of full-length SRC-1. This constitutes evidence for an in vivo role of SRC-1 in dimerization-induced activation by OR1/RXR.

Additionally, we show that the nuclear receptor-interacting protein RIP140 binds in vitro to OR1 and RXR with requirements distinct from those of SRC-1, and that binding of the two cofactors is competitive. Taken together, our results suggest a complex modulation of differentially induced transactivation by OR1/RXR coregulatory molecules.

This article has been cited by other articles:

				C. J Delvecchio and J. P Capone Protein kinase C {alpha} modulates liver X receptor {alpha} transactivation J. Endocrinol., April 1, 2008; 197(1): 121 - 130. [Abstract] [Full Text] [PDF]

				S. Talukdar, S. Bhatnagar, S. Dridi, and F. B. Hillgartner Chenodeoxycholic acid suppresses the activation of acetyl-coenzyme A carboxylase-{alpha} gene transcription by the liver X receptor agonist T0-901317 J. Lipid Res., December 1, 2007; 48(12): 2647 - 2663. [Abstract] [Full Text] [PDF]

				S. Talukdar and F. B. Hillgartner The mechanism mediating the activation of acetyl-coenzyme A carboxylase-{alpha} gene transcription by the liver X receptor agonist T0-901317 J. Lipid Res., November 1, 2006; 47(11): 2451 - 2461. [Abstract] [Full Text] [PDF]

				C. Yang, J. G. McDonald, A. Patel, Y. Zhang, M. Umetani, F. Xu, E. J. Westover, D. F. Covey, D. J. Mangelsdorf, J. C. Cohen, et al. Sterol Intermediates from Cholesterol Biosynthetic Pathway as Liver X Receptor Ligands J. Biol. Chem., September 22, 2006; 281(38): 27816 - 27826. [Abstract] [Full Text] [PDF]

				J. Huuskonen, P. E. Fielding, and C. J. Fielding Role of p160 Coactivator Complex in the Activation of Liver X Receptor Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 703 - 708. [Abstract] [Full Text] [PDF]

				A. W. Bull, K. R. Steffensen, J. Leers, and J. J. Rafter Activation of PPAR {gamma} in colon tumor cell lines by oxidized metabolites of linoleic acid, endogenous ligands for PPAR {gamma} Carcinogenesis, November 1, 2003; 24(11): 1717 - 1722. [Abstract] [Full Text] [PDF]

				J. M. Hall, C.-y. Chang, and D. P. McDonnell Development of Peptide Antagonists That Target Estrogen Receptor {beta}-Coactivator Interactions Mol. Endocrinol., December 1, 2000; 14(12): 2010 - 2023. [Abstract] [Full Text]

				Y. Luo, C.-p. Liang, and A. R. Tall The Orphan Nuclear Receptor LRH-1 Potentiates the Sterol-mediated Induction of the Human CETP Gene by Liver X Receptor J. Biol. Chem., June 29, 2001; 276(27): 24767 - 24773. [Abstract] [Full Text] [PDF]