Thyroid Hormone Receptor Coactivators and Corepressors

Abstract

In the absence of triiodothyronine (T3), thyroid hormone receptors (TRs) repress transcription of many genes; in the presence of T3, TRs activate transcription of those same genes. Both of these events are dependent on interactions between TRs and other nuclear proteins. TRs bind to specific DNA sequences, generally found in the 5' flanking regions of target genes. In the unliganded state, TRs interact with one of several corepressor proteins. These proteins, in turn, interact with a series of other proteins, which includes histone deacetylases. Histone deacetylation tightens chromatin structure, thus impairing access of critical transcription factors and thereby repressing transcription. In addition, corepressors may invoke mechanisms of gene repression independent of histone deacetylation. The binding of T3 causes a conformational change in the TR that results in release of the corepressor and recruitment of coactivator proteins. Several coactivator proteins appear to bind the ligand-occupied TR as a multiprotein complex. Opposite to corepressors, coactivators acetylate histones, thereby loosening chromatin structure and facilitating access of key transcription factors. Again, mechanisms independent of histone acetylation also may be involved. Overall, gene activation by T3 is a two-step process; removal of active repression, and induction of transcription to levels above the "neutral" state.

Involvement of chromatin and histone acetylation in the regulation of HIV-LTR by thyroid hormone receptor

“…It is generally believed that unliganded TR/RXR represses transcription by recruiting corepressor complexes while T3-bound TR/RXR activates transcription by recruiting coactivator complexes. The corepressor complexes contain histone deacetylases while some of the coactivator complexes have histone acetyltransferases activity but others do not [24][25][26][27][28]. This has led to the proposal of multiple models.…”

“…Interestingly, many coactivators such SRC-1 and C B P / p 3 0 0 a r e h i s t o n e a c e t y l a s e s (acetyltransferases) while corepressors such as SMRT and N-CoR can associate with histone deacetylase such as RPD3 [24][25][26][27]. To test the effect of histone acetylation on TR-dependent HIV LTR activity, we microinjected TR/RXR mRNAs and p4/5A into frog oocytes and treated the oocytes with trichostatin A (TSA), a specific histone deacetylase inhibitor [21].…”

Overexpression of thyroid hormone receptor beta1 is associated with thyrotropin receptor gene expression and proliferation in a human thyroid carcinoma cell line

“…Many nuclear cofactors are now known to participate in the complex regulation of gene expression (Koenig 1998). Among these cofactors, the corepressors complex with the unliganded TR to suppress the basal activities of genes positively regulated by T 3 , but facilitate transcription of genes negatively regulated by T 3 (Tagami et al 1997).…”

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

“…Wild-type TRs operate as hormone-regulated transcription factors that bind to specific DNA sequences (denoted thyroid response elements, or TREs) and regulate transcription of adjacent target genes (Mangelsdorf et al, 1995;Glass, 1996;Apriletti et al, 1998;Ribeiro et al, 1998;Beato and Klug, 2000;Zhang and Lazar, 2000). TRs bind to TREs, recruit corepressors (such as NCoR and SMRT), and typically repress transcription in the absence of hormone; conversely, the binding of T3 hormone induces a conformational change in TRs that results in corepressor release, the recruitment of coactivators (such as SRC-1), and transcriptional activation (Glass, 1996;Horwitz et al, 1996;Koenig, 1998;Ordentlich et al, 2001;Lee and Kang, 2002;. TRs can also regulate target genes indirectly through protein-protein contacts with other transcription factors.…”