Related Experiment Videos
Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action
Peter M Sadow1, Olivier Chassande, Karine Gauthier
1Departments of Medicine and Pathology, University of Chicago, Illinois 60637, USA.
Abstract:
Isoforms of the thyroid hormone receptor (TR)alpha and TRbeta genes mediate thyroid hormone action. How TR isoforms modulate tissue-specific thyroid hormone (TH) action remains largely unknown. The steroid receptor coactivator-1 (SRC-1) is among a group of transcriptional coactivator proteins that bind to TRs, along with other members of the nuclear receptor superfamily, and modulate the activity of genes regulated by TH. Mice deficient in SRC-1 possess decreased tissue responsiveness to TH and many steroid hormones; however, it is not known whether or not SRC-1-mediated activation of TH-regulated gene transcription in peripheral tissues, such as heart and liver, is TR isoform specific. We have generated mice deficient in TRalpha and SRC-1, as well as in TRbeta and SRC-1, and investigated thyroid function tests and effects of TH deprivation and TH treatment compared with wild-type (WT) mice or those deficient in either TR or SRC-1 alone. The data show that 1) in the absence of TRalpha or TRbeta, SRC-1 is important for normal growth; 2) SRC-1 modulates TRalpha and TRbeta effects on heart rate; 3) two new TRbeta-dependent markers of TH action in the liver have been identified, osteopontin (upregulated) and glutathione S-transferase (downregulated); and 4) SRC-1 may mediate the hypersensitivity to TH seen in liver of TRalpha-deficient mice.
Insights
Steroid receptor coactivator-1 (SRC-1) influences thyroid hormone (TH) action through thyroid hormone receptors (TRs). SRC-1 is crucial for normal growth and modulates TH effects on heart rate and liver gene expression in a TR isoform-specific manner.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Thyroid hormone receptors (TR)alpha and TRbeta mediate thyroid hormone (TH) action.
- Steroid receptor coactivator-1 (SRC-1) is a transcriptional coactivator that binds to TRs, modulating TH-regulated gene activity.
- The tissue-specific roles of TR isoforms and SRC-1 in TH action are not fully understood.
Purpose of the Study:
- To investigate the TR isoform specificity of SRC-1 in modulating TH action in peripheral tissues.
- To determine the roles of SRC-1 in TRalpha- and TRbeta-deficient mice under varying TH conditions.
Main Methods:
- Generation of mice deficient in TRalpha and SRC-1, and TRbeta and SRC-1.
- Comparison of thyroid function, TH deprivation, and TH treatment effects in genetically modified mice versus wild-type controls.
- Analysis of heart rate and liver gene expression markers (osteopontin, glutathione S-transferase).
Main Results:
- SRC-1 is essential for normal growth in the absence of either TRalpha or TRbeta.
- SRC-1 significantly modulates the effects of both TRalpha and TRbeta on heart rate.
- Novel TRbeta-dependent markers of TH action in the liver were identified: osteopontin (upregulated) and glutathione S-transferase (downregulated).
- SRC-1 may contribute to the observed hypersensitivity to TH in the liver of TRalpha-deficient mice.
Conclusions:
- SRC-1 plays a critical, isoform-specific role in mediating thyroid hormone action in peripheral tissues like the heart and liver.
- Understanding SRC-1 and TR isoform interactions is key to elucidating tissue-specific thyroid hormone regulation.
- Identification of new liver-specific TH action markers provides further insight into TRbeta function.