Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of T(3)-regulated transcription of genes in vivo.
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.
Takeuchi
Yoko
Y
Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
Murata
Yoshiharu
Y
Sadow
Peter
P
Hayashi
Yoshitaka
Y
Seo
Hisao
H
Xu
Jianming
J
O'Malley
Bert W
BW
Weiss
Roy E
RE
Refetoff
Samuel
S
D000469:Alkaline Phosphatase / Q000097:blood / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D002784:Cholesterol / Q000097:blood / Q000235:genetics; D003402:Creatine Kinase / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics* / Q000502:physiology*; D013006:Growth Hormone / Q000096:biosynthesis; D051548:Histone Acetyltransferases; D006728:Hormones / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D007037:Hypothyroidism / Q000139:chemically induced / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D010902:Pituitary Gland / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013972:Thyrotropin / Q000096:biosynthesis / Q000097:blood; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D014284:Triiodothyronine / Q000235:genetics* / Q000502:physiology*
D006728:Hormones; D012333:RNA, Messenger; D014157:Transcription Factors; D014284:Triiodothyronine; D013972:Thyrotropin; D013006:Growth Hormone; D002784:Cholesterol; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D003402:Creatine Kinase; D000469:Alkaline Phosphatase