Thyroid Hormone-independent Interaction between the Thyroid Hormone Receptor β2 Amino Terminus and Coactivators

Oberste-Berghaus, Corinna; Zanger, Kerstin; Hashimoto, Kazuhito; Cohen, Ronald N.; Hollenberg, Anthony N.; Wondisford, Fredric E.

doi:10.1074/jbc.275.3.1787

Cited by 72 publications

(45 citation statements)

References 44 publications

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“…Interestingly, the N-terminal domain of TR␤2, but not of TR␤1 or TR␣1, can also interact in a hormone-independent manner with a Gln-rich region located near the C terminus of all three p160 coactivators (30,32). This coactivator interaction likely contributes to the in vivo ability of TR␤2 to activate target gene expression in the absence of T 3 (32).…”

Section: The Unique N Terminus Of Tr␤2 Is Essential For the Enhanced mentioning

confidence: 99%

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

Privalsky

Lee²,

Hahm³

et al. 2009

Journal of Biological Chemistry

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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 TR␤2 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 TR␤2 parallel the ability of this isoform to bind p160 coactivators cooperatively through multiple contact surfaces; the more broadly expressed TR␤1 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 TR␤2 to recruit coactivator at limiting triiodothyronine concentrations. The PAS-B sequences also play an important role in coactivator binding by estrogen receptor-␣. 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.

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Section: The Unique N Terminus Of Tr␤2 Is Essential For the Enhanced mentioning

confidence: 99%

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

Privalsky

Lee²,

Hahm³

et al. 2009

Journal of Biological Chemistry

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“…Alternative promoter usage and differential splicing have been observed for many transcription factor genes, and in several instances this alters the structure of an activation domain. Most similar to SREBP-1, alternative promoters that result in N-terminal heterogeneity are common in the nuclear receptor family where different versions of an N-terminal constitutive activation domain (AF1) are produced (Zhu et al 1995;Oberste-Berghaus et al 2000;Huber et al 2002). However, in most cases, the real physiological significance of these variants has not been fully explored because most studies have focused on the nuclear receptor AF2 activation domain, which is located close to the ligand-binding domain at the C terminus.…”

Section: Transcriptional Activation By Srebpsmentioning

confidence: 99%

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

Osborne

Espenshade²

2009

Genes Dev.

234

249

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Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factors that are conserved from fungi to humans and are defined by two key features: a signature tyrosine residue in the DNA-binding domain, and a membrane-tethering domain that is a target for regulated proteolysis. Recent studies including genome-wide and model organism approaches indicate SREBPs coordinate cellular lipid metabolism with other cellular physiologic processes. These functions are broadly related as cellular adaptation to environmental changes ranging from nutrient fluctuations to toxin exposure. This review integrates classic features of the SREBP pathway with newer information regarding the regulation and sensing mechanisms that serve to assimilate different cellular physiologic processes for optimal function and growth.

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“…Mutagenesis studies (21,22) suggest that TR DNA binding to the half-site is required for negative regulation. Activation of these nTRE in the absence of T 3 is mediated by the N terminus of TR-␤2 via a mechanism involving binding of coactivator proteins (23,24).In contrast, some investigators have suggested that TR DNA binding is not required for negative regulation. This mechanism has been proposed to explain negative regulation of the TSH-␣ promoter where an nTRE has not been clearly identified (25,26).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Shibusawa

Hollenberg

Wondisford

2003

Journal of Biological Chemistry

Self Cite

117

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The ␤ isoform of thyroid hormone receptor (TR-␤) has a key role in the feedback regulation of the hypothalamic-pituitary-thyroid (H-P-T) axis. The mechanism of trans-repression of the hypothalamic thyrotropin-releasing hormone (TRH) and pituitary thyroid-stimulating hormone (TSH) subunit genes, however, remains poorly understood. A number of distinct mechanisms for TR-␤-mediated negative regulation by thyroid hormone have been proposed, including those that require and do not require DNA binding. To clarify the importance of DNA binding in negative regulation, we constructed a DNA-binding mutant of TR-␤ in which two amino acids within the P box were altered (GSG for EGG) to resemble that found in the glucocorticoid receptor (GR). We termed this mutant GS125, and as expected, it displayed low binding affinities for positive and negative thyroid hormone-response element (pTRE and nTRE, respectively) in gel-mobility shift assays. In transient transfection assays, the GS125 mutant abolished transactivation on three classic pTREs (DR؉4, LAP, and PAL) and all negatively regulated promoters in the H-P-T axis (TRH, TSH-␤, and TSH-␣). However, GS125 TR-␤ bound to a composite TR/GR-response element and was fully functional on this hybrid TR/GR-response element. Moreover, the GS125 TR-␤ mutant displayed normal interactions with transcriptional cofactors in mammalian twohybrid assays. These data do not support a DNA-binding independent mechanism for thyroid hormone negative regulation in the H-P-T axis.The synthesis and secretion of thyroid hormones are exquisitely regulated by a negative feedback system that involves the hypothalamus, pituitary, and thyroid gland (the hypothalamicpituitary-thyroid axis: H-P-T axis). 1 The synthesis of thyrotropin-releasing hormone (TRH), produced in the paraventricular nucleus of the hypothalamus, and the ␣ and ␤ subunits of thyrotropin (thyroid-stimulating hormone; TSH) in the anterior lobe of the pituitary is inhibited at the transcriptional level by thyroid hormone (T 3 ) (1-4). Negative regulation of gene expression by T 3 is an integral part of the function in the H-P-T axis, and these effects are mediated by the ␤ isoform of the thyroid hormone receptors (TR-␤). Of the ␤ isoforms, TR-␤2 is quantitatively and functionally more important than TR-␤1 in regulating the hypothalamus and pituitary (5-8). The molecular mechanisms responsible for TR-mediated negative regulation of target genes are not well understood.In the traditional model of TR action, TR regulates gene expression by binding to specific thyroid hormone-response elements (TRE) on target genes. A number of artificial and natural positive thyroid hormone-response elements (pTREs) have been described, and they can be classified based on the half-site arrangement in the element: DRϩ4, PAL, and LAP (LYS) (9 -11). On target genes negatively regulated by T 3 , response elements (nTREs) have been described in the TRH and TSH-␤ subunit genes (12-17). In these nTREs, TR bound as a monomer to widely spaced half-sites or in the case of...

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Thyroid Hormone-independent Interaction between the Thyroid Hormone Receptor β2 Amino Terminus and Coactivators

Cited by 72 publications

References 44 publications

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

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