Abstract
Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that play multiple roles in vertebrate endocrinology and development. TRs are expressed as a series of distinct receptor isoforms that mediate different biological functions. The TRbeta2 isoform is expressed primarily in the hypothalamus, pituitary, cochlea, and retina, and displays an enhanced response to hormone agonist relative to the other TR isoforms. We report here that the unusual transcriptional properties of TRbeta2 parallel the ability of this isoform to bind p160 coactivators cooperatively through multiple contact surfaces; the more broadly expressed TRbeta1 isoform, in contrast, utilizes a single contact mechanism. Intriguingly, the PAS-B domain in the p160 N terminus plays a previously unanticipated role in permitting TRbeta2 to recruit coactivator at limiting triiodothyronine concentrations. The PAS-B sequences also play an important role in coactivator binding by estrogen receptor-alpha. We propose that the PAS-B domain of the p160 coactivators is an important modulator of coactivator recruitment for a specific subset of nuclear receptors, permitting stronger transcriptional activation at lower hormone concentrations than would otherwise occur, and allowing isoform-specific mRNA splicing to customize the hormone response in different tissues.
Highlights
Thyroid hormone receptors (TRs)4 are members of a larger family of nuclear receptors that play multiple roles in vertebrate development, differentiation, and homeostasis [1,2,3]
The TR2 isoform in the hypothalamus and pituitary plays a crucial role in a negative feedback regulatory loop by which increases in circulating T3/T4 thyroid hormone levels result in suppression of thyroid releasing hormone and thyroid stimulating hormone synthesis, thereby restoring proper endocrine homeostasis [19, 20, 22, 25,26,27,28,29]
TR2 Displays an Enhanced Transcriptional Response to T3 Hormone Compared with the Other TR Isoforms Due to Its Unique N-terminal Domain—To compare the transcriptional properties of the different human TR isoforms (Fig. 1), we expressed each isoform in CV-1 cells together with a luciferase reporter containing a cognate direct repeat (DR)-4 response element [34]
Summary
Thyroid hormone receptors (TRs)4 are members of a larger family of nuclear receptors that play multiple roles in vertebrate development, differentiation, and homeostasis [1,2,3]. We report here that the enhanced transcriptional response of TR2 is closely paralleled by the enhanced ability of this isoform to bind to the p160 family of coactivators: SRC1 ( known as CoA-1), GRIP1 ( known as SRC2 or CoA-2), and activator of thyroid hormone receptor (ACTR) ( known as SRC3, or CoA-3).
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