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Different Configurations of Specific Thyroid Hormone Response Elements Mediate Opposite Effects of Thyroid Hormone and GC-1 on Gene Expression

Division of Endocrinology and Metabolism (B.G., E.A.S., W.H.D.), University of California, San Diego, La Jolla, California 92093; Department of Physiology and Biophysics (G.G.) and Department of Cell and Developmental Biology (A.S.M.), ICB University of Sao Paulo, 05508-900 Sao Paulo, Brazil; and Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology (G.C., T.S., J.D.B.), University of California, San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Wolfgang H. Dillmann, Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0618. E-mail: wdillman{at}ucsd.edu.

T₃ regulates transcription of the rat sarcoendoplasmic reticulum calcium ATPase in the heart. The T₃ effect is mediated by three differently configured T₃ response elements (TREs). Here we report the mutation of each individual TRE in the promoter and the contribution of each TRE on gene expression. Mutation of TRE1, a direct repeat element, exerted the strongest T₃ response, compared with TRE2 and TRE3, which are inverted palindromes. The isolated TRE2 and TRE3, which showed no response (TRE2) or were weakly positive with T₃ (TRE3), became strong negative regulatory elements with the T₃ analog GC-1. We found that TRE1 recruits corepressor complexes containing nuclear receptor corepressor and histone deacetylase 3 in the absence of ligand, and steroid receptor coactivator-1-containing coactivator complexes with both T₃ and GC-1. TRE3 bound the same corepressor complexes without ligand but showed only a weak association with steroid receptor coactivator-1 with T₃ and a strong association with corepressor complexes with GC-1. Thus, GC-1 appears to control cofactor association differentially on these two sarcoendoplasmic reticulum calcium ATPase TREs, which could be the mechanism of ligand-dependent transcriptional activation and repression observed with the isolated TRE1 and TRE3 elements. Because the x-ray crystal structures of GC-1 and T₃ complexed with the TR ligand binding domain are superimposable, the results imply that GC-1 and T₃ induce differential effects on the receptor that are not evident in the static structures but must occur in the dynamic setting of receptor function. These results have implications for selective modulation of receptor function by agonist ligands.

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