Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of t3-regulated transcription of genes in vivo

Yoko Takeuchi, Yoshiharu Murata, Peter Sadow, Yoshitaka Hayashi, S. E.O. Hisao, X. U. Jianming, Bert W. O'Malley, Roy E. Weiss, Samuel Refetoff

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42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1346-1352
Number of pages7
JournalEndocrinology
Volume143
Issue number4
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Endocrinology

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    Takeuchi, Y., Murata, Y., Sadow, P., Hayashi, Y., Hisao, S. E. O., Jianming, X. U., O'Malley, B. W., Weiss, R. E., & Refetoff, S. (2002). Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of t3-regulated transcription of genes in vivo. Endocrinology, 143(4), 1346-1352. https://doi.org/10.1210/endo.143.4.8730