Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of T(3)-regulated transcription of genes in vivo

Endocrinology. 2002 Apr;143(4):1346-52. doi: 10.1210/endo.143.4.8730.


Thyroid hormone exerts its biological effect by binding to a TR. Both liganded and unliganded TRs regulate the transcription of T(3)-responsive genes. Cofactors with activating or repressing function modulate the transcriptional regulation by TRs. We showed that steroid receptor coactivator 1 (SRC-1)-deficient mice (SRC-1(-/-)) exhibit partial resistance to thyroid hormone at the level of the pituitary thyrotrophs. To determine whether SRC-1 deficiency affects globally T(3)-dependent transcriptional regulation, we studied the effects of thyroid hormone deprivation and replacement on the expression of several genes in different tissues of SRC-1(-/-) and wild-type mice (SRC-1(+/+)). Thyroid hormone deficiency was induced by a low iodine diet (LoI) supplemented with propylthiouracil (PTU) for 2 wk. L-T(3) was injected ip for the last 4 d in one group (PTU+T(3) group), and another group (PTU group) received only vehicle. Levels of mRNAs for T(3)-responsive genes were determined by Northern blotting: GH and TSH beta in pituitary; type 1 iodothyronine 5'-deiodinase, spot 14 (S14), and malic enzyme in liver; and sarcoplasmic reticulum calcium adenosine triphosphatase 2 and myosin heavy chain alpha and beta in heart. Serum parameters, TSH, total cholesterol, creatine kinase, and alkaline phosphatase (AP), were also measured. Hypothyroidism produced a comparable increase in TSH beta mRNA in both genotypes, but its suppression by L-T(3) was attenuated in SRC-1(-/-) mice. In contrast, hypothyroidism failed to reduce S14 mRNA levels in SRC-1(-/-) mice. As a consequence, the response to L-T(3) was not observed in these mice. SRC-1 deficiency had no effect on the expression of the rest of the T(3)-responsive genes examined. Of the four serum parameters, the T(3)-mediated decrease in TSH and changes in AP were attenuated in SRC-1(-/-) mice. We conclude that SRC-1 deficiency altered the expression of only some of the T(3)-responsive genes. SRC-1 appears to be involved not only in transcriptional activation by liganded TRs, but also in the suppression by liganded or unliganded TRs. Some of the effects of SRC-1 may be TR isoform specific.

Publication types

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

MeSH terms

  • Alkaline Phosphatase / blood
  • Alkaline Phosphatase / genetics
  • Animals
  • Blotting, Northern
  • Cholesterol / blood
  • Cholesterol / genetics
  • Creatine Kinase / biosynthesis
  • Creatine Kinase / genetics
  • Gene Expression Regulation / genetics*
  • Gene Expression Regulation / physiology*
  • Growth Hormone / biosynthesis
  • Histone Acetyltransferases
  • Hormones / biosynthesis
  • Hormones / blood
  • Hormones / genetics
  • Hypothyroidism / chemically induced
  • Hypothyroidism / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism
  • Nuclear Receptor Coactivator 1
  • Pituitary Gland / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Thyrotropin / biosynthesis
  • Thyrotropin / blood
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Triiodothyronine / genetics*
  • Triiodothyronine / physiology*


  • Hormones
  • RNA, Messenger
  • Transcription Factors
  • Triiodothyronine
  • Thyrotropin
  • Growth Hormone
  • Cholesterol
  • Histone Acetyltransferases
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Creatine Kinase
  • Alkaline Phosphatase