Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone

EMBO J. 1999 Apr 1;18(7):1900-4. doi: 10.1093/emboj/18.7.1900.


Steroid receptor co-activator 1 (SRC-1) is a transcription co-factor that enhances the hormone-dependent action, mediated by the thyroid hormone (TH) receptor (TR) and other nuclear receptors. In vitro studies have shown that SRC-1 is necessary for the full expression of TH effect. SRC-1 knockout mice (SRC-1(-/-)) provide a model to examine the role of this co-activator on TH action in vivo. At baseline, SRC-1(-/-) mice display resistance to TH (RTH) as evidenced by a 2.5-fold elevation of serum TSH levels, despite a 50% increase in serum free TH levels as compared with wild-type (SRC-1(+/+)) mice. When mice were made hypothyroid, TSH levels increased, obliterating the difference between SRC-1(+/+) and SRC-1(-/-) mice observed at baseline. In contrast, the decline of TSH by treatment with L-triiodothyronine was severely blunted in SRC-1(-/-) mice. These data indicate that SRC-1 is not required for the upregulation of TSH in TH deficiency. However, SRC-1 enhances the sensitivity of TSH downregulation by TH. This is the first demonstration of RTH caused by a deficient co-factor other than TR. It supports the hypothesis that a putative defect in the SRC-1 gene or another co-factor could be the cause of RTH in humans without mutations in the TR genes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Drug Resistance
  • Female
  • Histone Acetyltransferases
  • Male
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Coactivator 1
  • Receptors, Steroid / deficiency*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Thyroid Hormones / metabolism
  • Thyroid Hormones / pharmacology*
  • Thyrotropin / blood
  • Thyroxine / blood
  • Trans-Activators / deficiency*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Triiodothyronine / blood
  • Triiodothyronine / pharmacology


  • Receptors, Steroid
  • Thyroid Hormones
  • Trans-Activators
  • Transcription Factors
  • Triiodothyronine
  • Thyrotropin
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Thyroxine