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Residues K128, 132, and 134 in the Thyroid Hormone Receptor- Are Essential for Receptor Acetylation and Activity

Departamento de Bioquímica (A.S.-P., O.M.-I., A.A.), Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Cinetificas-Universidad Autónoma de Madrid; and Centro de Investigaciones Oncológicas (M.M.-P.), 28029 Madrid, Spain

Address all correspondence and requests for reprints to: Aurora Sánchez-Pacheco and Ana Aranda, Instituto de Investigaciones Biomédicas A. Sols, C/Arturo Duperier, 4 28029 Madrid, Spain. E-mail: asanchez{at}iib.uam.es.

The thyroid hormone receptor (TR)- is a nuclear receptor that mediates both transrepression and ligand-dependent transactivation. Here we show that TR is posttranslationally modified by acetylation in response to its own ligand (T₃). Acetylation increases binding to DNA. Using mutagenesis, we identified three conserved lysine residues in the carboxi-terminal extension (CTE) of the DNA binding domain that are targets of the cAMP-response element-binding protein acetyltransferase. Substitution of these lysines by arginines in TR decreased ligand binding affinity and precluded ligand-dependent release of corepressors and recruitment of coactivators. The acetylation TR mutant lost the ability to transactivate even at high T₃ concentrations and acts as a dominant-negative inhibitor of wild-type TR activity. In addition, whereas native TR interferes with AP-1 function, the mutant is unable to mediate transrepression. Finally, TR suppresses NIH-3T3 fibroblast transformation by the Ras oncogene both in a ligand-dependent and -independent manner, but the CTE mutant is unable to mediate ligand-dependent repression of transformation. These results reveal a key role for the CTE region on acetylation, ligand affinity, transactivation, transrepression, and antitransforming properties of TR.