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

Roy E. Weiss, Jianming Xu, Guang Ning, Joachim Pohlenz, Bert W. O'Malley, Samuel Refetoff

Research output: Contribution to journalArticle

206 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1900-1904
Number of pages5
JournalEMBO Journal
Volume18
Issue number7
DOIs
StatePublished - Apr 1 1999

Keywords

  • Co-activator
  • Resistance to thyroid hormone
  • SRC-1
  • Thyroid hormone receptor
  • Thyrotropin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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