Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action

Abstract

of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action. Am J Physiol Endocrinol Metab 284: E36-E46, 2003. First published September 17, 2002 10.1152/ajpendo.00226. 2002.-Isoforms of the thyroid hormone receptor (TR)␣ and TR␤ 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 TR␣ and SRC-1, as well as in TR␤ 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 TR␣ or TR␤, SRC-1 is important for normal growth; 2) SRC-1 modulates TR␣ and TR␤ effects on heart rate; 3) two new TR␤-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 TR␣-deficient mice.knockout; resistance to thyroid hormone; thyrotropin THYROID HORMONE RECEPTOR (TR)␣ and TR␤ function as nuclear transcription factors that mediate thyroid hormone (TH) action. TRs bind to TH response elements on thyroid-responsive genes in association with transcriptional coregulators. Corepressors form part of a transcriptional complex and recruit histone deacetylases, reducing transcription (18, 40). The conformational change of TR produced by TH binding releases the corepressor and permits the recruitment and binding of a coactivator. The coactivator has a number of functions that may include intrinsic histone acetyltransferase activity, recruitment of histone acetyltransferases, and recruitment of additional transcription factors and RNA polymerase (21, 23). Several classes of nuclear coactivators have been described that are important in mediating the response of mammalian cells to thyroid as well as steroid and retinoid hormones (2,7,14,17,41,43), among which is the steroid receptor coactivator (SRC)-1, a member of the p160 family of coactivators (25).Because some genes are upregulated and others are downregulated by TH in the same cell, various theories have been proposed to explain the mechanism(s) of TR-modulated gene expression (see Ref. 44 for review). We propose that specificity of interaction among TR subtypes with particular cofactors may influence whether there is stimulation or inhibition of mRNA expression. Determination of the nature of interaction of TR subtypes with specific cofactors...

Hepatic gene expression patterns in thyroid hormone-treated hypothyroid rats

“…This is supported by recent findings of gene-specific effects of TR , TR and SRC-1 on T3-regulated gene expression (Flores-Morales et al 2002, Takeuchi et al 2002, Sadow et al 2003, although temporal expression patterns have not been analyzed in these studies. Furthermore, some genes are known to be endogenously regulated by T3 in vivo; however, a thyroid hormone response element (TRE) has not yet been identified within their regulatory elements (Table 2).…”

The nuclear corepressor, NCoR, regulates thyroid hormone action in vivo

“…We also examined the role of NCoR in the regulation of expression of genes known to be negatively regulated by T 3 (37,38). It has been speculated that corepressors may be paradoxically responsible for ligand-independent activation on negative targets (14,39).…”

Plasma protein regulation by thyroid hormone

“…Student's t-test; *P,0·05, **P,0·01, T 3 -vs Td-treated. Weitzel et al 2001, Flores-Morales et al 2002, Sadow et al 2003. It is possible that this subset of genes was not represented on the gene-chip or the delayed time course of induction by T 3 was not investigated.…”