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In Vivo Interaction of Steroid Receptor Coactivator (SRC)-1 and the Activation Function-2 Domain of the Thyroid Hormone Receptor (TR) β in TRβ E457A Knock-In and SRC-1 Knockout mice

Departments of Medicine (M.A., C.G., X.L., S.R., R.E.W.) and Pediatrics (S.R., R.E.W.), Committees on Genetics (S.R., R.E.W.) and Molecular Medicine (S.R.), The University of Chicago, Chicago, Illinois 60637; Instituto de Biofisica Carlos Chaga Filho (T.O.-C.), Universidade Federal do Rio de Janeiro, Rio de Janeiro RJ 21941-941, Brasil; and Metabolism Division (D.S.M., F.E.W.), Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Address all correspondence and requests for reprints to: Roy E. Weiss, M.D., Ph.D., The University of Chicago, MC 3090, Chicago, Illinois 60637. E-mail: rweiss{at}medicine.bsd.uchicago.edu.

The activation function-2 (AF-2) domain of the thyroid hormone (TH) receptor (TR)-β is a TH-dependent binding site for nuclear coactivators (NCoA), which modulate TH-dependent gene transcription. In contrast, the putative AF-1 domain is a TH-independent region interacting with NCoA. We determined the specificity of the AF-2 domain and NCoA interaction by evaluating thyroid function in mice with combined disruption of the AF-2 domain in TRβ, due to a point mutation (E457A), and deletion of one of the NCoAs, steroid receptor coactivator (SRC)-1. The E457A mutation was chosen because it abolishes NCoA recruitment in vitro while preserving normal TH binding and corepressor interactions resulting in resistance to TH. At baseline, disruption of SRC-1 in the homozygous knock-in (TRβ^E457A/E457A) mice worsened the degree of resistance to TH, resulting in increased serum T₄ and TSH. During TH deprivation, disruption of AF-2 and SRC-1 resulted in a TSH rise 50% of what was seen when AF-2 alone was removed, suggesting that SRC-1 was interacting outside of the AF-2 domain. Therefore, 1) during TH deprivation, SRC-1 is necessary for activating the hypothalamic-pituitary-thyroid axis; 2) ligand-dependent repression of TSH requires an intact AF-2; and 3) SRC-1 may interact with the another region of the TRβ or the TR to regulate TH action in the pituitary. This report demonstrates the dual interaction of NCoA in vivo: the TH-independent up-regulation possibly through another domain and TH-dependent down-regulation through the AF-2 domain.