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Submitted on May 26, 2005
Accepted on July 26, 2005
Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA 92093, USA; Department of Cell and Developmental Biology ICB, University of Sao Paulo, Brazil; Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California, San Francisco, California, USA
* To whom correspondence should be addressed. E-mail: wdillman{at}ucsd.edu.
Thyroid hormone (T3) regulates transcription of the rat sarco-endoplasmic reticulum calcium ATPase (SERCa2) 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 NCoR and HDAC3 in the absence of ligand, and SRC-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 SRC-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 SERCa2 TREs, which could be the mechanism of ligand dependent transcriptional activation and repression observed with the isolated TRE1 and TRE3 elements. Since the x-ray crystal structures of GC-1 and T3 complexed with the TR ligand binding domain (LBD) are superimposible, 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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