11897691

pubmed:Citation

4

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.

eng

AIM

MEDLINE

0013-7227

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NLM

1346-52

pubmed-meshheading:11897691-Alkaline Phosphatase, pubmed-meshheading:11897691-Animals, pubmed-meshheading:11897691-Blotting, Northern, pubmed-meshheading:11897691-Cholesterol, pubmed-meshheading:11897691-Creatine Kinase, pubmed-meshheading:11897691-Gene Expression Regulation, pubmed-meshheading:11897691-Growth Hormone, pubmed-meshheading:11897691-Histone Acetyltransferases, pubmed-meshheading:11897691-Hormones, pubmed-meshheading:11897691-Hypothyroidism, pubmed-meshheading:11897691-Liver, pubmed-meshheading:11897691-Mice, pubmed-meshheading:11897691-Mice, Knockout, pubmed-meshheading:11897691-Myocardium, pubmed-meshheading:11897691-Nuclear Receptor Coactivator 1, pubmed-meshheading:11897691-Pituitary Gland, pubmed-meshheading:11897691-RNA, Messenger, pubmed-meshheading:11897691-Thyrotropin, pubmed-meshheading:11897691-Transcription Factors, pubmed-meshheading:11897691-Triiodothyronine

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

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