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J Biol Chem, Vol. 275, Issue 15, 11507-11513, April 14, 2000

Post-transcriptional Regulation of Thyroid Hormone Receptor Expression by cis-Acting Sequences and a Naturally Occurring Antisense RNA*

Michelle L. HastingsDagger §, Hema A. IngleDagger , Mitchell A. Lazar, and Stephen H. MunroeDagger ||

From the Dagger  Department of Biology, Marquette University, Milwaukee, Wisconsin 53201 and the  Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Thyroid hormone (T3) coordinates growth, differentiation, and metabolism by binding to nuclear thyroid hormone receptors (TRs). The TRalpha gene encodes T3-activated TRalpha 1 (NR1A1a) as well as an antagonistic, non-T3-binding alternatively spliced product, TRalpha 2 (NR1A1b). Thus, the TRalpha 1/TRalpha 2 ratio is a critical determinant of T3 action. However, the mechanisms underlying this post-transcriptional regulation are unknown. We have identified a non-consensus, TRalpha 2-specific 5' splice site and conserved intronic sequences as key determinants of TRalpha mRNA processing. In addition to these cis-acting elements, a novel regulatory feature is the orphan receptor RevErbAalpha (NR1D1) gene, which is transcribed from the opposite direction at the same locus and overlaps the TRalpha 2 coding region. RevErbAalpha gene expression correlates with a high TRalpha 1/TRalpha 2 ratio in a number of tissues. Here we demonstrate that coexpression of RevErbAalpha and TRalpha regulates the TRalpha 1/TRalpha 2 ratio in intact cells. Thus, both cis- and trans-regulatory mechanisms contribute to cell-specific post-transcriptional regulation of TR gene expression and T3 action.

* This work was supported in part by National Institutes of Health Grants DK 48034 and GM 55922 (to S. H. M.) and DK45586 (to M. A. L.).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.

§ Supported by a predoctoral fellowship from the Arthur J. Schmitt Foundation. Current address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.

|| To whom correspondence should be addressed: Dept. of Biology, Wehr Life Sciences Bldg., Marquette University, P. O. Box 1881, Milwaukee, WI 53201. Tel.: 414-288-1485; Fax: 414-288-7357; E-mail: stephen.munroe@marquette.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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