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Molecular and Cellular Biology, April 2000, p. 2604-2618, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Orphan Nuclear Receptor Ear-2 Is a Negative Coregulator for Thyroid Hormone Nuclear Receptor Function

Xu-guang Zhu,1 Kyung Soo Park,1 Masahiro Kaneshige,1 Manoj K. Bhat,1,dagger Qihong Zhu,2 Cary N. Mariash,2 Peter McPhie,3 and Sheue-yann Cheng1,*

Laboratory of Molecular Biology, National Cancer Institute,1 and Laboratory of Biochemical Pharmacology, National Institutes of Diabetes, Digestive, and Kidney Diseases,3 National Institutes of Health, Bethesda, Maryland 20892, and Division of Endocrinology and Diabetes, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 554552

Received 22 November 1999/Returned for modification 23 December 1999/Accepted 5 January 2000

Thyroid hormone (T3) nuclear receptors (TR) are ligand-dependent transcription factors which regulate growth, differentiation, and development. One emerging hypothesis suggests that TR mediate these diverse effects via a large network of coregulators. Recently, we found that TR-mediated transcriptional responses varied in six cell lines derived from different tissues. We therefore used human TR subtype beta 1 (TRbeta 1) as bait to search for coregulators in human colon carcinoma RKO cells with a yeast two-hybrid system. RKO cells exhibited T3-dependent and -independent transcriptional activation. One of the three positive clones was identified as Ear-2, which is a distant member of the chick ovalbumin upstream promoter-transcription factors of the orphan nuclear receptor family. The physical interaction between Ear-2 and TRbeta 1 was further confirmed by specific binding of Ear-2 to glutathione S-transferase-TRbeta 1. In addition, Ear-2 was found to associate with TRbeta 1 in cells. As a result of this physical interaction, binding of TRbeta 1 to the T3 response elements was inhibited. Using reporter systems, we found that both the basal activation and the T3-dependent activation mediated by TRbeta 1 were repressed by Ear-2 in CV1 cells. In RKO cells, however, the T3-independent transcriptional activity was more sensitive to the repression effect of Ear-2 than the T3-dependent transcriptional activity. The repression effect of Ear-2 was reversed by steroid hormone receptor coactivator 1. These results suggest that TR-mediated responses reflect a balance of corepressors and coactivators in cells. These findings further strengthen the hypothesis that the diverse activities of TR are achieved via a large network of coregulators that includes Ear-2.

* Corresponding author. Mailing address: Building 37, Room 2D24, 37 Convent Dr. MSC 4255, Bethesda, MD 20892-4255. Phone: (301) 496-4280. Fax: (301) 480-9676. E-mail: sycheng{at}helix.nih.gov.

dagger Present address: National Center for Cell Science (NCCS), NCCS Complex, Pune University, Campus Ganeshkhind, Pune 411 007, India.

Molecular and Cellular Biology, April 2000, p. 2604-2618, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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