Steroid Receptor Coactivator-1 Deficiency Causes Variable Alterations in the Modulation of T3-Regulated Transcription of Genes in Vivo

Abstract

Thyroid hormone exerts its biological effect by binding to a TR. Both liganded and unliganded TRs regulate the transcription of T3-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 T3-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-T3 was injected ip for the last 4 d in one group (PTU+T3 group), and another group (PTU group) received only vehicle. Levels of mRNAs for T3-responsive genes were determined by Northern blotting: GH and TSHβ 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 α and β in heart. Serum parameters, TSH, total cholesterol, creatine kinase, and alkaline phosphatase (AP), were also measured. Hypothyroidism produced a comparable increase in TSHβ mRNA in both genotypes, but its suppression by l-T3 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-T3 was not observed in these mice. SRC-1 deficiency had no effect on the expression of the rest of the T3-responsive genes examined. Of the four serum parameters, the T3-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 T3-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.