This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart 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 Harding, H. P. Articles by Lazar, M. A. Search for Related Content PubMed PubMed Citation Articles by Harding, H. P. Articles by Lazar, M. A.

Transcriptional Activation and Repression by ROR, an Orphan Nuclear Receptor Required for Cerebellar Development

Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Mutation of the orphan nuclear receptor ROR results in a severe impairment of cerebellar development by unknown mechanisms. We have found that ROR activates transcription from only a subset of sites to which it binds strongly as a monomer. ROR also selectively binds as a homodimer to a direct repeat of this monomer site with a 2-bp spacing between the AGGTCA sequences (Rev-DR2 site) and is a much more potent transcriptional activator on this site than on monomer sites or other direct repeats. To better understand the transcriptional regulatory functions of ROR, we fused its C terminus to a heterologous DNA-binding domain. Mutational analysis revealed that ROR contains both transcriptional activation and transcriptional repression domains, with the repression domain being more active in some cell types. The abilities of ROR polypeptides to repress transcription correlate with their abilities to interact with the nuclear receptor corepressors N-CoR and SMRT in vitro. However, the AF2 region of ROR inhibits corepressor interaction on DNA, consistent with the lack of repression by the full-length receptor. Thus, transcriptional regulation by ROR is complex and likely to be regulated in a cell type- and target gene-specific manner.

This article has been cited by other articles:

				T. Wada, H. S. Kang, A. M. Jetten, and W. Xie The Emerging Role of Nuclear Receptor ROR{alpha} and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation Experimental Biology and Medicine, October 1, 2008; 233(10): 1191 - 1201. [Abstract] [Full Text] [PDF]

				S. Hummasti and P. Tontonoz Adopting New Orphans into the Family of Metabolic Regulators Mol. Endocrinol., August 1, 2008; 22(8): 1743 - 1753. [Abstract] [Full Text] [PDF]

				T. Wada, H. S. Kang, M. Angers, H. Gong, S. Bhatia, S. Khadem, S. Ren, E. Ellis, S. C. Strom, A. M. Jetten, et al. Identification of Oxysterol 7{alpha}-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor {alpha} (ROR{alpha}) (NR1F1) Target Gene and a Functional Cross-Talk between ROR{alpha} and Liver X Receptor (NR1H3) Mol. Pharmacol., March 1, 2008; 73(3): 891 - 899. [Abstract] [Full Text] [PDF]

				G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors Pharmacol. Rev., December 1, 2006; 58(4): 798 - 836. [Abstract] [Full Text] [PDF]

				J. Wang, L. Yin, and M. A. Lazar The Orphan Nuclear Receptor Rev-erb{alpha} Regulates Circadian Expression of Plasminogen Activator Inhibitor Type 1 J. Biol. Chem., November 10, 2006; 281(45): 33842 - 33848. [Abstract] [Full Text] [PDF]

				A. Genoux, H. Dehondt, A. Helleboid-Chapman, C. Duhem, D. W. Hum, G. Martin, L. A. Pennacchio, B. Staels, J. Fruchart-Najib, and J.-C. Fruchart Transcriptional Regulation of Apolipoprotein A5 Gene Expression by the Nuclear Receptor ROR{alpha} Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1186 - 1192. [Abstract] [Full Text] [PDF]

				Y.-T. Chen, L. L. Collins, H. Uno, and C. Chang Deficits in Motor Coordination with Aberrant Cerebellar Development in Mice Lacking Testicular Orphan Nuclear Receptor 4 Mol. Cell. Biol., April 1, 2005; 25(7): 2722 - 2732. [Abstract] [Full Text] [PDF]

				F. Boukhtouche, J. Mariani, and A. Tedgui The "CholesteROR" Protective Pathway in the Vascular System Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 637 - 643. [Abstract] [Full Text] [PDF]

				A. N. Moraitis and V. Giguere The Co-repressor Hairless Protects ROR{alpha} Orphan Nuclear Receptor from Proteasome-mediated Degradation J. Biol. Chem., December 26, 2003; 278(52): 52511 - 52518. [Abstract] [Full Text] [PDF]

				E. Raspe, G. Mautino, C. Duval, C. Fontaine, H. Duez, O. Barbier, D. Monte, J. Fruchart, J.-C. Fruchart, and B. Staels Transcriptional Regulation of Human Rev-erbalpha Gene Expression by the Orphan Nuclear Receptor Retinoic Acid-related Orphan Receptor alpha J. Biol. Chem., December 13, 2002; 277(51): 49275 - 49281. [Abstract] [Full Text] [PDF]

				A. N. Moraitis, V. Giguere, and C. C. Thompson Novel Mechanism of Nuclear Receptor Corepressor Interaction Dictated by Activation Function 2 Helix Determinants Mol. Cell. Biol., October 1, 2002; 22(19): 6831 - 6841. [Abstract] [Full Text] [PDF]

				A. Traven, L. Staresincic, M. Arneric, and M. Sopta The yeast protein Xtc1 functions as a direct transcriptional repressor Nucleic Acids Res., June 1, 2002; 30(11): 2358 - 2364. [Abstract] [Full Text] [PDF]

				J. M. Harris, P. Lau, S. L. Chen, and G. E. O. Muscat Characterization of the Retinoid Orphan-Related Receptor-{alpha} Coactivator Binding Interface: A Structural Basis for Ligand-Independent Transcription Mol. Endocrinol., May 1, 2002; 16(5): 998 - 1012. [Abstract] [Full Text] [PDF]

				K. Gawlas and H. G. Stunnenberg Differential transcription of the orphan receptor ROR{beta} in nuclear extracts derived from Neuro2A and HeLa cells Nucleic Acids Res., August 15, 2001; 29(16): 3424 - 3432. [Abstract] [Full Text] [PDF]

				B. Gebelein and R. Urrutia Sequence-Specific Transcriptional Repression by KS1, a Multiple-Zinc-Finger-Kruppel-Associated Box Protein Mol. Cell. Biol., February 1, 2001; 21(3): 928 - 939. [Abstract] [Full Text]

				P. H. Giangrande, E. A. Kimbrel, D. P. Edwards, and D. P. McDonnell The Opposing Transcriptional Activities of the Two Isoforms of the Human Progesterone Receptor Are Due to Differential Cofactor Binding Mol. Cell. Biol., May 1, 2000; 20(9): 3102 - 3115. [Abstract] [Full Text]

				C. Rachez, M. Gamble, C.-P. B. Chang, G. B. Atkins, M. A. Lazar, and L. P. Freedman The DRIP Complex and SRC-1/p160 Coactivators Share Similar Nuclear Receptor Binding Determinants but Constitute Functionally Distinct Complexes Mol. Cell. Biol., April 15, 2000; 20(8): 2718 - 2726. [Abstract] [Full Text]

				B. R. Sevetson, J. Svaren, and J. Milbrandt A Novel Activation Function for NAB Proteins in EGR-dependent Transcription of the Luteinizing Hormone beta Gene J. Biol. Chem., March 24, 2000; 275(13): 9749 - 9757. [Abstract] [Full Text] [PDF]

				G. B. Atkins, X. Hu, M. G. Guenther, C. Rachez, L. P. Freedman, and M. A. Lazar Coactivators for the Orphan Nuclear Receptor ROR{alpha} Mol. Endocrinol., September 1, 1999; 13(9): 1550 - 1557. [Abstract] [Full Text]

				A. N. Moraitis and V. Giguère Transition from Monomeric to Homodimeric DNA Binding by Nuclear Receptors: Identification of RevErbA{alpha} Determinants Required for ROR{alpha} Homodimer Complex Formation Mol. Endocrinol., March 1, 1999; 13(3): 431 - 439. [Abstract] [Full Text]

				N. Koibuchi, Y. Liu, H. Fukuda, A. Takeshita, P. M. Yen, and W. W. Chin ROR{alpha} Augments Thyroid Hormone Receptor-Mediated Transcriptional Activation Endocrinology, March 1, 1999; 140(3): 1356 - 1364. [Abstract] [Full Text]

				M.-H. Hsu, C. N. A. Palmer, W. Song, K. J. Griffin, and E. F. Johnson A Carboxyl-terminal Extension of the Zinc Finger Domain Contributes to the Specificity and Polarity of Peroxisome Proliferator-activated Receptor DNA Binding J. Biol. Chem., October 23, 1998; 273(43): 27988 - 27997. [Abstract] [Full Text] [PDF]

				J. Zhang, M. G. Guenther, R. W. Carthew, and M. A. Lazar Proteasomal regulation of nuclear receptor corepressor-mediated repression Genes & Dev., June 15, 1998; 12(12): 1775 - 1780. [Abstract] [Full Text]

				P. A. Crawford, C. Dorn, Y. Sadovsky, and J. Milbrandt Nuclear Receptor DAX-1 Recruits Nuclear Receptor Corepressor N-CoR to Steroidogenic Factor 1 Mol. Cell. Biol., May 1, 1998; 18(5): 2949 - 2956. [Abstract] [Full Text]

				E. Raspe, H. Duez, P. Gervois, C. Fievet, J.-C. Fruchart, S. Besnard, J. Mariani, A. Tedgui, and B. Staels Transcriptional Regulation of Apolipoprotein C-III Gene Expression by the Orphan Nuclear Receptor RORalpha J. Biol. Chem., January 19, 2001; 276(4): 2865 - 2871. [Abstract] [Full Text] [PDF]