In vivo interaction of steroid receptor coactivator (SRC)-1 and the activation function-2 domain of the thyroid hormone receptor (TR) βin TRβ E457A knock-in and SRC-1 knockout mice

Manuela Alonso, Charles Goodwin, Xiaohui Liao, Tania Ortiga-Carvalho, Danielle S. Machado, Fredric E. Wondisford, Samuel Refetoff, Roy E Weiss

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The activation function-2 (AF-2) domain of the thyroid hormone (TH) receptor (TR)-β is a THdependent 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 (TRβE457A/E457A) mice worsened the degree of resistance to TH, resulting in increased serum T 4 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 TRβor the TRαto 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 downregulation through the AF-2 domain.

Original languageEnglish (US)
Pages (from-to)3927-3934
Number of pages8
JournalEndocrinology
Volume150
Issue number8
DOIs
StatePublished - Aug 2009
Externally publishedYes

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Nuclear Receptor Coactivator 1
Thyroid Hormone Receptors
Thyroid Hormones
Knockout Mice
Thyroid Hormone Resistance Syndrome
Thyroid Gland
Co-Repressor Proteins
Point Mutation
Up-Regulation
Down-Regulation
Binding Sites
Ligands

ASJC Scopus subject areas

  • Endocrinology

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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) βin TRβ E457A knock-in and SRC-1 knockout mice. / Alonso, Manuela; Goodwin, Charles; Liao, Xiaohui; Ortiga-Carvalho, Tania; Machado, Danielle S.; Wondisford, Fredric E.; Refetoff, Samuel; Weiss, Roy E.

In: Endocrinology, Vol. 150, No. 8, 08.2009, p. 3927-3934.

Research output: Contribution to journalArticle

Alonso, Manuela ; Goodwin, Charles ; Liao, Xiaohui ; Ortiga-Carvalho, Tania ; Machado, Danielle S. ; Wondisford, Fredric E. ; Refetoff, Samuel ; Weiss, Roy E. / In vivo interaction of steroid receptor coactivator (SRC)-1 and the activation function-2 domain of the thyroid hormone receptor (TR) βin TRβ E457A knock-in and SRC-1 knockout mice. In: Endocrinology. 2009 ; Vol. 150, No. 8. pp. 3927-3934.
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abstract = "The activation function-2 (AF-2) domain of the thyroid hormone (TH) receptor (TR)-β is a THdependent 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 (TRβE457A/E457A) mice worsened the degree of resistance to TH, resulting in increased serum T 4 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 TRβor the TRαto 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 downregulation through the AF-2 domain.",
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AU - Alonso, Manuela

AU - Goodwin, Charles

AU - Liao, Xiaohui

AU - Ortiga-Carvalho, Tania

AU - Machado, Danielle S.

AU - Wondisford, Fredric E.

AU - Refetoff, Samuel

AU - Weiss, Roy E

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