Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1900-1904 |
| Number of pages | 5 |
| Journal | EMBO Journal |
| Volume | 18 |
| Issue number | 7 |
| State | Published - Apr 1 1999 |
| Externally published | Yes |
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Keywords
- Co-activator
- Resistance to thyroid hormone
- SRC-1
- Thyroid hormone receptor
- Thyrotropin
ASJC Scopus subject areas
- Genetics
- Cell Biology
Cite this
Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone. / Weiss, Roy E; Xu, Jianming; Ning, Guang; Pohlenz, Joachim; O'Malley, Bert W.; Refetoff, Samuel.
In: EMBO Journal, Vol. 18, No. 7, 01.04.1999, p. 1900-1904.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone
AU - Weiss, Roy E
AU - Xu, Jianming
AU - Ning, Guang
AU - Pohlenz, Joachim
AU - O'Malley, Bert W.
AU - Refetoff, Samuel
PY - 1999/4/1
Y1 - 1999/4/1
N2 - 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.
AB - 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.
KW - Co-activator
KW - Resistance to thyroid hormone
KW - SRC-1
KW - Thyroid hormone receptor
KW - Thyrotropin
UR - http://www.scopus.com/inward/record.url?scp=0033118328&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033118328&partnerID=8YFLogxK
M3 - Article
C2 - 10202153
AN - SCOPUS:0033118328
VL - 18
SP - 1900
EP - 1904
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 7
ER -