Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone.
Steroid receptor co-activator 1 (SRC-1) is a transcription co-factor that enhances the hormone-dependent action, mediated by the thyroid hormone (TH) receptor (TR) and other nuclear receptors. In vitro studies have shown that SRC-1 is necessary for the full expression of TH effect. SRC-1 knockout mice (SRC-1(-/-)) provide a model to examine the role of this co-activator on TH action in vivo. At baseline, SRC-1(-/-) mice display resistance to TH (RTH) as evidenced by a 2.5-fold elevation of serum TSH levels, despite a 50% increase in serum free TH levels as compared with wild-type (SRC-1(+/+)) mice. When mice were made hypothyroid, TSH levels increased, obliterating the difference between SRC-1(+/+) and SRC-1(-/-) mice observed at baseline. In contrast, the decline of TSH by treatment with L-triiodothyronine was severely blunted in SRC-1(-/-) mice. These data indicate that SRC-1 is not required for the upregulation of TSH in TH deficiency. However, SRC-1 enhances the sensitivity of TSH downregulation by TH. This is the first demonstration of RTH caused by a deficient co-factor other than TR. It supports the hypothesis that a putative defect in the SRC-1 gene or another co-factor could be the cause of RTH in humans without mutations in the TR genes.
Weiss
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Department of Medicine,Jr Mental Retardation Research Center, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA. rweiss@medicine.bsd.uchicago.edu
Xu
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Ning
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Pohlenz
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O'Malley
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Refetoff
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D000818:Animals; D004351:Drug Resistance; D005260:Female; D051548:Histone Acetyltransferases; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1; D011987:Receptors, Steroid / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism / Q000494:pharmacology*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000097:blood / Q000494:pharmacology
D011987:Receptors, Steroid; D013963:Thyroid Hormones; D015534:Trans-Activators; D014157:Transcription Factors; D014284:Triiodothyronine; D013972:Thyrotropin; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D013974:Thyroxine